TW201200594A - Novel immunotherapy against several tumors including gastrointestinal and gastric cancer - Google Patents

Abstract

The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to 95 novel peptide sequences and their variants derived from HLA class I molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.

Description

201200594 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the invention relates to immunotherapy for cancer. The present invention also relates to a tumor-associated cytotoxic T helper cell (ctl) peptide epitope for use alone or in combination with other tumor-associated peptides (active pharmaceutical ingredients of the anti-tumor immune response vaccine complex). The present invention relates to 33 novel peptide sequences and variants thereof derived from human tumor HLA class I molecules useful in vaccine compositions useful for eliciting an anti-tumor immune response. [Prior Art] Gastric cancer is a disease in which malignant cells form in the stomach wall. Gastric cancer can develop in any part of the stomach and may spread throughout the stomach and other organs; especially the esophagus, lungs and liver. Gastric cancer is the fourth most common cancer in the world. In 2002, there were 930,000 confirmed cases. The high mortality rate of gastric cancer (~80 million per year) makes it the second most common cause of cancer deaths in the world after lung cancer. The disease is more common in men's more common in Asian countries and in developing China. (http://www.who.int/mediacentre/factsheets/fs297/en/.) In the United States, gastric cancer accounts for approximately 2% (255 cases) of all new cancer cases each year, but is more common in other countries. In South Korea, gastric cancer is the first cancer, accounting for 20.8% of malignant tumors. In Japan, gastric cancer remains the most common cancer in men. In the United States, approximately 8,000 men and i3000 women are diagnosed with stomach cancer each year. Most are 7 years old or older. Lunar cancer is the fourth most common cancer in the world, second only to lung cancer, breast 154845.doc 201200594 Cancer, colon cancer and rectal cancer. In addition, gastric cancer remains the second most common cause of cancer death. According to the American Cancer Society, there were one million new cases in 2007, nearly 7% of which occurred in developing countries, and about 800,000 deaths (http://www.cancer.org/downloads/STT/Global_Facts_and

Figure s_2007_rev2.pdf.) There is a huge geographical difference in the global incidence of this disease. The incidence of the disease is highest in parts of Asia and South America and lowest in North America. According to records, the mortality rate of the disease is the highest in Chile, Japan, South America and the former Soviet Union. Except for early detection in Japan (a limited method in Korea), screening is not performed in most parts of the world, so gastric cancer is usually advanced in the diagnosis. As a result, stomach cancer still poses significant challenges for healthcare professionals. The risk factors for gastric cancer are Helicobacter pylori infection, smoking, high intake of salt, and other dietary factors. A small number of gastric cancers (1% to 3%) are associated with genetic susceptibility syndromes in gastric cancer. In the family of autosomal dominant susceptibility to diffuse gastric cancer, approximately 25% of baboon-gene mutations occur. This subgroup of gastric cancer is called hereditary diffuse gastric cancer. This may be beneficial in providing genetic counseling and considering prophylactic gastrectomy in young, asymptomatic carriers with truncated truncation. Month 2 consists of 3 layers of tissue. The membrane (inner) layer, the muscle (intermediate) layer and the poly Membrane (outermost) layer. Gastric cancer first occurs in the inner wall of the mucosa, and spreads to the outer layer with growth. The four kinds of quasi-therapeutic methods can treat gastric cancer. The treatment of gastric cancer includes surgery, chemotherapy, radiotherapy or radiotherapy and chemotherapy. Surgery is the main treatment for gastric cancer. The purpose of the hand (4) is to perform a complete resection and make the margin negative (R0 I54845.doc 201200594 resection). However, approximately 50% of local gastric cancers are unable to undergo R〇 resection. Ri resection indicates that residual cancer cells can be found under the microscope (positive margin of resection), and ruler 2 excision indicates residual cancer cells visible to the naked eye, but the disease has not metastasized. Patient outcomes depend on the initial stage of diagnosis (nccn Oncology Practice Guide τΜ). For patients with π-stage disease, the 5-year survival rate after therapeutic surgical resection is 30-50% ‘P) patients are 1〇_25%. These patients are highly likely to have local and systemic recurrences. Metastasis occurs in 80-90% of patients with gastric cancer, and the 6-month survival rate is 65% in patients who are not diagnosed earlier, and less than 〇5〇/〇 in patients diagnosed later. Therefore, there is still a need for a new treatment regimen that promotes the well-being of patients who are safe and effective, and who do not use chemotherapy drugs or may cause serious side effects: gastric cancer, prostate (epithelial) cancer, oral cancer, oral scales Cell carcinoma (0SCC), acute myeloid leukemia (AML), Helicobacter pylori-induced malt lymphoma, colon (epithelial) carcinoma/colorectal cancer, glioblastoma, non-small cell lung cancer (NSCLC), cervix (epithelial) Cancer, human breast cancer, prostate cancer, colon cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, ovarian cancer, hepatocellular carcinoma, liver cancer, brain tumors of different phenotypes, acute lymphoblastic leukemia (all), leukemia, lung cancer , Ewing's sarcoma, endometrial cancer, head and neck squamous cell carcinoma, laryngeal epithelial cancer, esophageal cancer, oral (epithelial) cancer, bladder cancer, ovarian (epithelial) cancer, renal cell carcinoma, atypical meningioma, nipple Malignant solid tumors such as thyroid carcinoma, brain tumor, ductal carcinoma of the parotid gland, papillary carcinoma, extranodal T/NK cell lymphoma, non-Hodgkin's lymphoma, lung cancer and breast cancer, And other tumors. I54845.doc 201200594 The present invention employs a peptide stimulating the immune system to act as an anti-tumor preparation in a non-invasive manner. [Explanation] Whether or not the immune response can be stimulated depends on the presence or absence of an antigen considered to be a foreign body by the host immune system. The presence of tumor-associated antigens was found to increase the likelihood of using the host immune system to interfere with tumor growth. For cancer immunotherapy, various mechanisms for utilizing the humoral and cellular immunity of the immune system are currently being explored. Specific elements of cellular immune responses specifically recognize and destroy tumor cells. Cytotoxic D-cells (CTLs) isolated from tumor infiltrating cell populations or peripheral blood indicate that these cells play an important role in the natural immune defense of cancer. In particular, CD8-positive T cells (TCD8+) play an important role in this response. TCD8 recognizes major histocompatibility of amino acid residues from 8 to 1 源自-derived proteins or cytoplasmic defective ribosome products (DRIP). A class J molecule contained in a peptide contained in a sex complex (MHC). Human MHC molecules are also known as human leukocyte-antigen (hla). There are two types of MHC molecules: MHC-I molecules that are found on most cells with nuclei. The MHC molecules are composed of a -1 重 1 heavy chain and a β 2 -microglobulin (MHC-steroid receptor) or "and a 0 chain (MHC_n receptor). Its three-position structure forms a binding groove for non-covalent interaction with the peptide. Mhc class I molecules are mainly produced by endogenous proteins, DRIPS and larger peptides. MHC steroids are mainly found on professional antigen presenting cells (C) and are mainly presented by A? during endocytosis. A peptide that occupies and is subsequently protected by an exogenous or transmembrane protein. The complex of peptide and mhc ι 154845.doc 201200594 is recognized by CD8-positive cytotoxic T lymphocytes loaded with the corresponding TCR (T cell receptor), while the complex of peptide and MHC class II molecules is loaded with CD4 of the corresponding TCR. Positive helper T cells were identified. It is well known in the art that TCR, peptide and MHC are thus present in stoichiometric amounts of 1:1:1. For the trigger (priming) cellular immune response, it must bind to the MHC molecule. This process relies on the allele of the MHC molecule and the specific polymorphism of the peptide amino acid sequence. The MHC-steroid-binding peptide is usually 2 amino acid residues in length and binds to each other in the groove corresponding to the MHC molecule. The sequence of action typically contains two conserved residues ("anchor"). Thus, each MHC allele has a "binding motif" to determine which peptides specifically bind to the binding groove. In MHC-steroid-dependent immune responses, peptides not only bind to certain MHC-steroidal molecules expressed by tumor cells, but they must also be recognized by the tau cell-specific T cell receptor (Tcr). The antigens recognized by tumor-specific cytotoxic T lymphocytes, ie their epitopes' may be molecules derived from all protein types, such as enzymes, receptors, transcription factors 4, which are expressed in cells of the corresponding tumor, and Its expression is up-regulated compared to homologous cells. Tumor-associated peptides are currently classified into the following major groups: a) Cancer-testis antigen: The first confirmed TAA that T cells can recognize belongs to this class of antigens' because their members are expressed in histologically different human tumors, normal tissues. Medium, only in testicular spermatocytes/spermatogonia, occasionally in the placenta 'so' it was originally called the cancer-testis (CT) antigen. Since testicular cells do not express HLA class I and π-type molecules, in normal tissues, 154845.doc 201200594 These antigens are not recognized by tau cells and are therefore immunologically considered to be tumor specific. A well-known example of a CT antigen is a member of the River Family or NY-ESO-1. b) Differentiation antigens: Tumors and normal tissues (from which the tumor originates) contain TAA. Most TAAs are found in melanoma and normal black & primordial cells. These melanocyte lineage-associated proteins are involved in the biosynthesis of melanin, so these proteins are not tumor-specific, but are still widely used in cancer immunotherapy. Examples include, but are not limited to, melanoma tyrosinase and Melan-A/MART-1 or psA of prostate cancer. c) Over-expressed TAA: TAAs with widely expressed genes are detected in histologically distinct tumors as well as in many normal tissues, with generally low expression levels. "Maybe many tables processed and potentially presented by normal tissues." The level is below the threshold level of T cell recognition, and their overexpression in tumor cells can trigger an anti-cancer response by breaking previously established tolerance. Typical examples of such TAAs are Her-2/neu, survivin, telomerase or WT1. d) Tumor-specific antigens: These unique TAAs are produced by mutations in normal genes (such as calcium-catenin, CDK4, etc.). Some of these molecular changes are associated with 'tumor transformation and/or progression. Tumor-specific antigens generally induce a strong immune response in the absence of a risk of a positive Φ tissue with an immune response. On the other hand, these TAAs are in most cases only associated with the exact tumor in which TAA has been identified, and usually do not share TAA between many individual tumors. e) TAA produced by abnormal post-translational modification: such TAA may be produced by a protein that is neither specific nor overexpressed in the tumor, but it still has a tumor correlation of 154845.doc 201200594 (this correlation is mainly due to tumor Due to active post-translational processing). Such TAA results from a change in the thiolation pattern, resulting in a tumor producing a novel epitope against MUC 1 or causing events such as protein splicing during degradation' which may or may not have tumor specificity. f) Tumor virus proteins: These TTAs are viral proteins that play a key role in carcinogenesis and, because they are foreign proteins (non-human proteins), are capable of eliciting a tau cell response. Examples of such proteins are human papillomavirus type VI, E6 and E7, which are expressed in cervical cancer. Special conditions must be established for proteins that are recognized as cytotoxic T lymphocytes as tumor-specific antigens or related antigens and for treatment. The antigen should be expressed primarily by tumor cells, not by normal healthy tissues, or by a relatively small number of expressions. More suitably, the corresponding antigen not only appears in one tumor, but also in concentration (i.e., the number of corresponding peptide copies per cell). Tumor-specific antigens and tumor-associated antigens are often proteins derived from the direct conversion of normal cells to tumor cells that occur as a function of cell cycle control or apoptosis inhibition. In addition, these downstream targets of proteins that directly cause transformation events may be up-regulated and may therefore be indirectly related to tumors. These tumor indirect related antigens may also be a light standard for preventing inoculation methods (Singh-Jasuja H., Emmerich N. P.,

Rammensee H. G., Cancer Immunol. Immunother. 2004 Mar; 453(3): 187-95). In both cases, it is essential that the epitope of the amino acid sequence is present, so that the peptide derived from the tumor-associated antigen ("immunogenic peptide") can cause a tau cell reaction in vitro or in vivo. . Essentially any peptide that binds to an MHC molecule may act as a τ I54845.doc 201200594 cell epitope. The premise of inducing a tau cell response in vitro or in vivo is the presence of sputum cells with corresponding TCR and no immunological tolerance to this particular epitope. Therefore TAA疋 develops the starting point of tumor vaccines. Methods of identification and characterization are based on the use of patients or healthy subjects or based on differential transcriptional or differential expression patterns between tumors and normal tissue peptides. However, the identification of genes that are overexpressed or selectively expressed in tumor tissues or human tumor cell lines does not provide accurate information on the use of antigens transcribed by these genes in immunotherapy. This is because there is a corresponding tau cell that must exist and the immune pairing for this particular epitope must be absent or at a minimum, since only a portion of the epitopes of these antigens are suitable for this application. Therefore, it is very important to select only those peptides from which the eggs are overexpressed or selectively expressed and these peptides are combined with MHC molecules which can find antagonistic functional tau cells. This functional butyl cell is defined as a butyl cell that is capable of clonal expansion and is capable of performing effector functions ("effector T cells") after stimulation with a specific antigen. Helper T cells play an important role in the organization of CTL effector functions against tumor immunity. The helper tau cell epitope that triggers the TH1 cell response supports the effector functions of cD8 13⁄4 sex killer T cells, including cytotoxic functions that act directly on tumor cells (the tumor cell surface shows tumor-associated peptide/MHC complexes). Such tumor-associated T helper peptide epitopes, either alone or in combination with other tumor associated peptides, can serve as active pharmaceutical ingredients for stimulating an anti-tumor immune response vaccine composition. I54845.doc 201200594 [Embodiment] Unless otherwise stated, all terms used herein are defined as follows. As used herein, the term "peptide" refers to a series of amino acid residues, typically linked to each other by a peptide bond between an alpha-amino acid and a carbonyl group of an adjacent amino acid. These peptides are preferably 9 amino acids in length, but may be as long as 8 amino acids in length to be 1, 11, 12, 13 or 14 amino acids in length. The term "oligopeptide" as used herein refers to a series of amino acids. The residue is typically linked to each other by a peptide bond between the alpha-amino acid and the carbonyl group of an adjacent amino acid. The length of the oligopeptide is not critical to the invention as long as the correct epitope is maintained in the oligopeptide. Typically, the oligopeptide is less than about 3 amino acid residues in length, and is about 14 amino acids long. The term "polypeptide" refers to a series of amino acid residues, usually linked by a peptide bond between a heart amino acid and a carbonyl group of an adjacent amino acid. The length of the polypeptide is not critical to the invention as long as the correct epitope is maintained. In contrast to the term peptide or oligopeptide, the term "polypeptide" refers to a molecule comprising more than about 30 amino acid residues. A peptide, a peptide, a protein or a nucleotide encoding the molecule has "immunogenicity" (and thus an "immunogen" in the present invention) if it can induce an immune response. In the context of the present invention, a more specific definition of immunogenicity is the ability to induce a sputum cell response. Therefore, an "immunogen" is a molecule capable of inducing an immune response, and in the case of the present invention, a molecule capable of inducing a sputum cell reaction. The "epitope" of tau cells requires a short peptide that binds to MHC class I receptors to form a ternary complex (^111 (: class 1 〇1 chain, P_2_microglobulin 154845.doc -12-) 201200594 and its shape] can be recognized by a T cell carrying a matched buty cell receptor that binds to the MHC/peptide complex with corresponding affinity. The typical length of the molecule bound to the MHC class I molecule is 8-14 amino acids, the most Typically 9 amino acids in length. In humans, there are three different gene loci that encode MHC class I molecules (human MHC molecules are also designated human leukocyte antigens (HLA)): HLA-A, HLA-B, and JJLA-C. HLA -A*01, HLA-A*02 and HLA-A*024 are examples of different MHC class I alleles that can be expressed from these loci. Table 1 · HLA-A*024 and the most common HLA*A 〇2402 Serum type expression frequency F ° frequency according to the Hardy-Weinberg formula F = 1_(1_Gf)2 used by ^^"丨 et al. (M〇ri et ai. i〇17_27), from the US population Derived from the body frequency. For more information, please refer to

Chanock et al. (Chanock et al. 1211-23). The global expression of HLA*24 and A*24〇2 expression frequency allele population based on the allele frequency phenotype A*24 Filipino 65% A*24 Russian Nenets 61% A*2402曰 59% A*24 Malaysian 58% A*2402 Filipino 54% A*24 Indian 47% A*24 Korean 40% A*24 Sri Lankan 37% 154845.doc 13 201200594 A*24 Chinese 32 % A*2402 Indian 29% A*24 Western Australian 22% A*24 American 22% A*24 Russian Samara 20% A*24 South American 20% A*24 European 18% The DNA sequence includes both single-stranded DNA and double-stranded DNA. Thus, unless otherwise indicated herein, a particular sequence is the single stranded DNA of the sequence, the duplex (double stranded DNA) of the sequence and its complement, and the complement of the sequence. The term "coding region" refers to the portion of the gene that naturally or normally encodes the expression product of the gene in the natural genomic environment of the gene, i.e., the region in vivo encoding the native expression product of the gene. The coding region can be derived from a non-mutated ("normal") gene, a mutated gene or an aberrant gene, and even from a DNA sequence, and can be synthesized in the laboratory using DNA synthesis methods well known in the art. The term "nucleotide sequence" refers to a heteropolymer of deoxynucleotides. The nucleotide sequence encoding a particular peptide, oligopeptide or polypeptide may be a natural nucleotide sequence or a synthetic nucleotide sequence. In general, a DNA fragment encoding a peptide, a polypeptide, and a protein of the present invention consists of a cDNA fragment and a short oligonucleotide adaptor, or a series of oligonucleotides to provide a synthetic gene capable of containing the derived microorganism. Or a recombinant transcription unit of a regulatory element of a viral operon is expressed. The term "expression product" refers to a polypeptide or protein which is a translation product of a nucleic acid sequence encoding an equivalent of a gene and a 154845.doc 14 8 201200594 code-degraded and thus encoding the same amino acid. The term "fragment", when referring to a coding sequence, refers to a portion of a DNA comprising a non-intact coding region, the expression product of which has substantially the same biological function or activity as the entire encoded expression product. The term "DNA fragment" refers to a DNA polymer that exists as a separate fragment or as a component of a larger DNA structure that is obtained in substantially pure form from at least one DNA that has been isolated, ie, free of Contaminating endogenous materials, and the amount or concentration obtained can be used to identify, manipulate, and recover the fragment and its component nucleotide sequences using standard biochemical methods, such as the use of cloning vectors. Such fragments exist in the form of an open reading frame (not interrupted by an internal untranslated sequence) or an intron (usually presented in a eukaryotic gene). Untranslated DNA sequences may be present in the downstream of the open reading frame where they do not interfere with manipulation or expression of the coding region. The term "primer" refers to a short nucleic acid sequence that is paired with a DNA strand and provides a free 3'-〇H terminus at the point where the DNA polymerase begins to synthesize the DNA strand. The term "promoter" refers to a region of DNA that is involved in the binding of RNA polymerase to initiate transcription. The term "isolated" means that a substance is removed from its original environment (for example, if it is naturally occurring, it is a natural environment). For example, a natural nucleotide or polypeptide in a living animal is not isolated, but the isolated nucleic acid or polymorphism from the natural system = or all coexisting substances is isolated. Such a polynucleotide may be a vector. A portion of and/or such a multi-nuclear 154845.doc -15-201200594 acid and polypeptide may be part of a composition, and since the vector or composition is not part of its natural environment, it is (iv) separated. . The polynucleic acid and recombinant or immunogenic polypeptides disclosed herein may also exist in the form of . The term "purification" does not require absolute purity; it is only a relative definition and can be understood by those skilled in the art of highly purified or partially purified art. For example, each of the various clones that have been purified from the 1st treasury that has been purified by conventional methods to have electrophoretic homogeneity. It is explicitly contemplated to purify the starting material or natural material by at least one order of magnitude, preferably two or three orders of magnitude, more preferably four or five orders of magnitude. Further, it is expressly contemplated that the purity of the polypeptide is preferably 99.999%' or at least 99.99% or 99 9%; and is suitably 99% by weight or more. Nucleic acid and polypeptide expression products according to the present invention, as well as expression vectors comprising such nucleic acids and/or polypeptides, may exist in "concentrated form." The term "concentrated" as used herein means that the concentration of the material is at least about 2, 5, 10, 100 or 1000 times its natural concentration. It is advantageous to be 0. 01% by weight, preferably at least 〇·1. %. It is also explicitly considered to be about 0.5%, 1%, 5%, 10% and 20 by weight. /. Concentrated preparation. Sequences, Configurations 'Vectors, clones, and other materials comprising the invention may be advantageously present in concentrated or isolated form. The term "active fragment" refers to a fragment that produces an immune response (ie, has immunogenic activity)' whether administered alone or alternatively with a suitable adjuvant, such as a mammal, such as a rabbit or mouse. Also included is human; this immune response takes the form of stimulating a tau cell response in an animal (eg, human) body 154845.doc 201200594. Alternatively, an "active fragment" can also be used to induce an in vitro sputum cell response. As used herein, the terms "p", "segment", "fragment" and "fragment", when used in connection with a polypeptide, refer to a contiguous sequence of residues, such as amino acids. A residue whose sequence forms a subset of a larger sequence. For example, if a polypeptide is treated with either peptide endo-peptidase (e.g., trypsin or chymotrypsin), the oligopeptide obtained by the treatment will represent a portion, segment or fragment of the starting polypeptide. This means that any such fragment must contain a segment, fragment or portion that is substantially identical (if not identical) to the sequence of SEQ ID ΝΟ: 1 to 33 as part of its amino acid sequence, which corresponds to SEQ m NO: 1 to 33 natural protein or "parent" protein. When used in connection with a polynucleotide, these terms are used to treat the product produced by the polynucleotide with any common endonuclease. According to the present invention, the term "percentage of equivalence" or "equivalent percentage", if it refers to a sequence, means a sequence to be compared ("converted sequence") and a sequence of the sequence or claim (r reference sequence). Alignment » will be compared to the sequence of the sequence or claim by comparison. Then calculate the percentage of equivalence according to the following formula: Equivalent percentage = 1 〇〇 KC / R)] where c is the number of differences between the reference sequence and the sequence being compared between the reference sequence and the sequence being compared, where Each domain or amino acid sequence in the reference sequence has no corresponding alignment domain or amino acid in the sequence being compared; (11) each gap in the reference sequence, and each pair in the reference sequence of 154845.doc 201200594 (ni) The quasi-domain or amino acid differs from the aligned domain or amino acid in the compared sequence, ie, constitutes a difference; and R is the reference sequence and the length of the aligned sequence to generate any gap in the reference sequence is also calculated as a domain Or the number of domain or amino acid in the reference sequence of the amino acid. If an alignment between the "converted sequence" and the "reference sequence" is equal to or greater than the specified minimum equivalence percentage as described above, then The compared sequence and the reference sequence have a specified minimum percentage of equivalence, although there may be a percentage of equivalence calculated as described herein above Alignment below a specified percentage of equivalence. If not otherwise stated, then the original peptides disclosed herein can be modified by substituting one or more residues at different (possibly selective) sites within the peptide bond. This substitution may be conservative, for example, where one amino acid is replaced by another amino acid having a similar structure and character, such as one of the hydrophobic amino acids being replaced by another hydrophobic amino acid. The more conservative substitutions are the same or similar. Size- and chemical-acid substitutions between amino acids, such as 'leucine, are replaced by isoleucine. In the study of sequence variations in natural homologous protein families, substitution of certain amino acids is often more tolerant than other amino acids. Amino acids often exhibit a correlation with the similarity between the size, charge, polarity and hydrophobicity of the original amino acid, which is the basis for determining "conservative substitutions." In this context, 'conservative substitutions' are defined as one of the following five groups. Internal exchange. Group 1 - small aliphatic, non-polar or slightly polar residues (Ala, Ser·, Thr, Pro, Gly); group 2_polar, negatively charged residue and I54845.doc -18- 201200594 its indoleamine (Asp, Asn, Glu, Gin); group 3-polar, positively charged residue (His , Arg, Lys); group 4-large aliphatic non-polar residue (Met, Leu, ne, Val, Cys) and 5-quinone aromatic residue (Phe, Tyr, Trp). Substitution may involve the replacement of one amino acid by another amino acid that has similar characteristics but differs in size, such as alanine substituted with an isoleucine residue. Highly unconservative substitutions may involve an acidic amino acid being Substituted by an amino acid that is polar or even basic. However, this "radical" substitution cannot be considered invalid and is not considered because the chemical action is not completely predictable, and radical substitution may bring it Unexpected accidental effects in simple chemical principles. Of course, this substitution may involve other structures than ordinary L_amino acids. Therefore, D-amino acids may be substituted by the amino acids commonly found in the antigenic peptides of the present invention, and are still within the scope of the present disclosure, in addition, amino acids having non-standard R groups (ie, 'two common ones except for natural proteins' R groups other than amino acids can also be used for the purpose of substitution to produce immunogens and immunogenic polypeptides according to the invention. If substitutions at more than one position are found to result in the antigenic activity of the peptide being substantially equal to or greater than the values defined below, the combination of these substitutions is tested to determine if the combined substitution results in a superposition or synergistic effect on the antigenicity of the peptide. The position in the peptide that is simultaneously substituted may not exceed four at most. The "T cell response" refers to the specific diffusion and initiation of the PF function induced by a peptide in vitro or in vivo. For MHC class I-restricted CTLs, the effector function may be a target cell that lyses peptide pulsed, peptide precursor pulsed or native peptide, secretes cytokine, preferably peptide-induced stem 154845.doc 19 201200594 Interferon-γ TNF-α or IL-2, a secretory effector molecule, preferably a peptide or a granzyme or perforin induced by degranulation. Preferably, when the peptide-specific CTL of any of SEQ ID NOs. 1 to 33 is detected compared to the substituted peptide, if the solubility of the substituted peptide reaches a maximum of half relative to the background peptide, the peptide concentration is not More than about j mM ' is preferably no more than about 1 μΜ, more preferably no more than about 1 nM, still more preferably no more than about 100 pM', and most preferably no more than about 1 μm. It is also preferred that the 'substituent peptide is recognized by more than one CTL, at least two, more preferably three. Thus, an epitope described herein may be identical to a natural tumor-associated epitope or a tumor-specific epitope, and may also include different peptides of no more than 4 residues from a reference peptide as long as they have substantially the same antigenic activity, ie can. Whether the immunotherapy method stimulates the immune response depends on the presence or absence of an antigen that is considered a foreign body by the host immune system. The discovery of tumor-associated antigens has increased the likelihood of using the host immune system to interfere with tumor growth. For cancer immunotherapy, various mechanisms for controlling humoral and cellular immunity in the immune system are being explored. Specific elements of cellular immune responses specifically recognize and destroy tumor cells. The cytotoxic τ-fine moon b (CTL) isolated from tumor infiltrating cell populations or peripheral blood suggests that these cells play an important role in the natural immune defense of cancer. (d) CD8-positive T cells play an important role in this reaction, and they can produce the major histocompatibility of 8 to 12 basal acid residues derived from the ribosome-deficient ribosomal product (DRIP). Compound 154845.doc 201200594 The class i molecule contained in the peptide contained in the body_c). Human MHC molecules are also known as human leukocyte-antigen (HLA). MHC-steroidal molecules are found in the nucleus presenting cells that are produced by cleavage of major endogenous, cytoplasmic or nuclear proteins, and PS and larger peptide proteins. However, peptides derived from endosomal structures or exogenous sources often also find m molecules on MHCM-like molecules. (IV) The mode of presentation is referred to in the literature as cross-presentation. Special conditions must be met for the recognition of cytotoxic T lymphocytes as tumor-specific antigens or related antigens and for the treatment of (iv) egg self-quality. The antigen should be expressed primarily by tumor cells, whereas normal healthy tissues do not express or express a small amount at all. More suitably, the corresponding antigen not only appears in one tumor, but also at a high concentration (i.e., the number of corresponding peptide copies per cell). Tumor-specific antigens and tumor-associated antigens are usually proteins that are directly involved in the transformation of normal cells into tumor cells due to functions such as cell cycle regulation or apoptosis. In addition, these downstream targets that directly cause transformation may also be up-regulated and therefore indirectly related to the tumor. These indirect tumor-associated antigens may also be targets for vaccination methods. It is essential that in both cases an epitope of the aminoguanidine sequence of the antigen is present, such a peptide derived from a tumor-associated antigen ("immunogenic peptide") can cause a T cell response in vitro or in vivo. Basically, any peptide that binds to an MHC molecule may act as a tau cell epitope. The premise of inducing T cell responses in vitro or in vivo is the presence of T cells with the corresponding TCR and the absence of immunological tolerance to this particular epitope. 0 154845.doc -21 - 201200594 Therefore TAA疋 develops the starting point for the identification of tumor vaccines and The method of characterizing taa is based on the use of CTLs in patients or healthy subjects, or on the generation of differential transcriptional or differential expression patterns between tumors and positive*s (Lemmel et al. 450-54; Weinschenk et al. 5818). -27). However, the recognition of genes that are overexpressed or selectively expressed in tumor tissues or human tumor cell lines does not provide accurate information on the use of antigens transcribed by these genes in immunotherapy. This is because tau cells with corresponding tCr must be present and the immune tolerance to this particular epitope must be absent or at a minimum, so only a subset of the epitopes of these antigens are suitable for this application. Therefore, it is important to select only those proteins that are overexpressed or selectively expressed and that these peptides are presented in conjunction with MHC molecules that can find antagonistic functional T cells. This functional T cell is derogated as a T cell that can be cloned and expanded to be able to perform effector functions ("effector T cells") after stimulation with a specific antigen. Helper T cells play an important role in the organization of the ctl effector function of anti-tumor immunity. The helper t cell epitope that triggers the TH! cell response supports the effector function of CD8-positive killer T cells, including the cytotoxic function that directly acts on tumor cells (the tumor cell surface shows tumor-associated peptide/MHC complexes). Thus, tumor-associated tau helper epitopes alone or in combination with other tumor-associated peptides can be used as active pharmaceutical ingredients for vaccine compounds that stimulate anti-tumor immune responses. Because CD8 and CD4-dependent responses work together and synergistically to promote anti-tumor effects', CD8-positive CTLs (MHC-I molecules) or CD4-positive CTLs (MHC-II molecules) recognize and identify tumor-associated antigens for the development of tumors 154,845. Doc •22· 201200594 The vaccine is very important. Therefore, it has been proposed to formulate a peptide composition containing a complex with any of the mhc complexes. Considering the serious side effects and costs associated with the treatment of cancer, there is an urgent need for more (4) (4) and methods. Therefore, it is often necessary to identify other factors that represent cancer: other factors, especially stomach cancer. In addition, it is often necessary to determine the factors that can be used to treat cancer, especially gastric cancer. In addition, S has no definitive treatment design and can be used in patients with gastric cancer who have biochemical recurrence after radical prostatectomy. The recurrence is usually caused by local advanced tumor growth in the tumor remaining in the primary site. There is a need for new treatments that reduce morbidity and have comparable efficacy to existing treatments. The present invention proposes peptides which are advantageous for the treatment of gastric cancer and other tumors which overexpress the peptide of the present invention. These peptides are directly shown by mass spectrometry and are naturally presented by human HLA knives in human primary gastric cancer samples (see Example ^ and Figure 1). Derived peptide-derived genes show high overexpression compared to normal tissues in gastric cancer, renal cell carcinoma 'colon cancer, non-small cell lung cancer, adenocarcinoma, prostate cancer, benign tumors, and malignant melanoma (see Example 2). And Figure 2), which indicates that these peptides are highly associated with tumors, ie, these peptides are abundantly present in tumor tissues' without being presented to normal tissues. HLA-binding peptides are recognized by the immune system, particularly tau lymphocytes/tau cells. The sputum cells can destroy cells that present the recognized HLA/peptide complex (eg, gastric cancer cells that present the derived peptide). All of the peptides of the invention have been shown to have the ability to stimulate T cell responses (see Example 3 and Figure 3). Thus, the peptides can be used to produce a 154845.doc -23-201200594 epidemic response in a patient' thus sufficient to destroy tumor cells. The patient's immune response can be induced by directly administering to the patient the peptide or precursor material (e.g., lengthening the peptide, protein, or nucleic acid encoding the peptide), preferably in combination with an immunogenic formulation. The immune response derived from the therapeutic vaccine is expected to be highly specific against tumor cells' because the target peptide of the present invention has a small number of copies presented on normal tissues, preventing the patient from developing a poor autoimmune response against normal cells. risk. Pharmaceutical compositions include peptides in free form or in the form of a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed peptide wherein the peptide is modified by the acid salt or the domain salt of the agent. For example, an acid salt is prepared by reacting with a suitable acid using a free radical (usually where the neutral form of the drug has a neutral _NH2 group). Acids suitable for the preparation of acid salts include organic acids such as acetic acid, propionic acid, hydroxy acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, and stupid Capric acid, cinnamic acid, mandelic acid, methanesulfonic acid, sulfonic acid, benzenesulfonic acid, salicylic acid, etc., and inorganic acids such as hydrochloric acid, gas desert acid, sulfuric acid, nitric acid and acid. In contrast, domain salt formulations which can be presented in a form of acidic groups are prepared using pharmaceutically acceptable domains such as sodium hydroxide, guanidinium oxyhydroxide, hydrazine hydroxide, cesium hydroxide, trimethylamine and the like. In a particularly preferred embodiment, the pharmaceutical composition comprises a peptide in the form of acetic acid (acetate) or hydrochloric acid (vapor). The peptides of the invention can also be used for diagnosis in addition to being used to treat cancer. Since peptides are produced by lean, and it has been determined that these peptides do not exist in normal tissues, these peptides can be used to diagnose the presence or absence of cancer. I54845.doc -24· 201200594 ,. The use of 3_to (four) peptide in gas slices can help pathologists. Detection of this condition by antibodies, mass spectrometry, or other methods known in the art can allow the pathologist to determine whether the tissue is malignant, inflammatory, or sedative: the presentation of a squamous group enables classification or further division of the diseased tissue Subclass 0 Detection of peptides in diseased specimens allows for the identification of immune system treatments. 'Specially|JX if Τ_lymphatic sac is known or predicted to be related to the mechanism of action. Deletion of MHC expression is a mechanism that fully demonstrates which infected malignant cells evade immune surveillance. Therefore, the presentation of peptides indicates that the analyzed cells did not utilize this mechanism. The peptide is used to react a lymphocyte to a peptide (e.g., a tau cell reaction), or a reaction of an antibody to a peptide complexed with a peptide or an MHC molecule. These lymphocyte responses can be used as prognostic indicators to determine whether further treatment is needed. These responses can also be used as surrogate markers in immunotherapy to induce lymphocyte responses in different ways, such as inoculation of protein vaccines, nucleic acids, and autologous material 'lymphocyte adoptive transfer. In gene therapy, the response of lymphocytes to peptides can be considered in the assessment of side effects. Lymphocyte response monitoring is also a valuable tool in follow-up examination of transplant therapy, for example, for the detection of graft versus host and host versus graft disease. The form can be used to generate and develop specific antibodies against MHC/peptide complexes. These antibodies can be used to treat toxins or radioactive materials to the diseased tissue. Another use of these antibodies is to target radionuclides to diseased tissue for imaging purposes (e.g., ρΕΤ). This can help detect small metastases or confirm the size and exact location of the diseased tissue. 154845.doc -25· 201200594 In addition, these TUMAPs can be used to validate the pathologist's diagnosis of cancer based on biopsy samples. Table 2 shows the peptides according to the invention, their respective SEQ ID NOs, and the source proteins from which these peptides may be produced. All peptides bind to the HLA A*024 allele. Table 2: Peptides in the present invention

SE〇ID NO: Peptide code sequence Source protein 1 CDC2-001 LYQILQGIVF CDK1 2 ASPM-002 SYNPLWLRI ASPM 3 UCHL5-001 NYLPFIMEL UCHL5 4 MET-006 SYIDVLPEF MET 5 PROM 1-001 SYIIDPLNL PROM1 6 MMP11-001 VWSDVTPLTF MMP 11 7 MST1R -001 NYLLYVSNF MST1R 8 NFYB-001 VYTTSYQQI NFYB 9 SMC4-001 HYKPTPLYF SMC4 10 UQCRB-001 YYNAAGFNKL UQCRB 11 PPAP2C-001 AYLVYTDRL PPAP2C 12 AVL9-001 FYISPVNKL AVL9 13 NUF2-001 VYGIRLEHF NUF2 14 ABL1-001 TYGNLLDYL ABL1 15 MUC6-001 NYEETFPHI MUC6 16 ASPM-001 RYLWATVTI ASPM 17 EPHA2-005 VYFSKSEQL EPHA2 18 MMP3-001 VFIFKGNQF MMP3 19 NUF2-002 RFLSGIINF NUF2 20 PLK4-001 QYASRFVQL PLK4 21 ATAD2-002 KYLTVKDYL ATAD2 22 COL12A1-001 VYNPTPNSL COL12A1 23 COL6A3-001 SYLQAANAL COL6A3 24 FANCI-001 FYQPKIQQF FANCI 154845.doc -26- 201200594

25 RPS11-001 YYKNIGLGF RPS11 26 ATAD2-001 AYAIIKEEL ATAD2 27 ATAD2-003 LYPEVFEKF ATAD2 28 HSP90B1-001 KYNDTFWKEF HSP90B1 29 SIAH2-001 VFDTAIAHLF SIAH2 30 SLC6A6-001 VYPNWAIGL SLC6A6 31 IQGAP3-001 VYKVVGNLL IQGAP3 32 ERBB3-001 VYIEKNDKL ERBB3 33 KIF2C -001 IYNGKLFDLL KIF2C Other HLA A*02 peptides of interest in the present invention:

SE〇ID NO: Peptide code sequence source protein 34 CCDC88A- 001 QYIDKLNEL CCDC88A 35 CCNB1-003 MYMTVSIIDRF CCNB1 36 CCND2-001 RYLPQCSYF CCND2 37 CCNE2-001 IYAPKLQEF CCNE2 38 CEA-010 IYPDASLLI CEACAM1, CEACAM5, CEACAM6 39 CLCN3-001 VYLLNSTTL CLCN3 40 DNAJC10-001 IYLEVIHNL DNAJC 10 41 DNAJC10-002 AYPTVKFYF 42 EIF2S3-001 IFSKIVSLF EIF2S3, LOC255308 43 EIF3L-001 YYYVGFAYL EIF3L, LOC340947 44 EPPK1-001 RYLEGTSCI EPPK1 45 ERBB2-001 TYLPTNASLSF ERBB2 46 GPR39-001 SYATLLHVL GPR39 47 ITGB4-001 DYTIGFGKF ITGB4 48 LCN2-001 SYNVTSVLF LCN2 49 SDHC-001 SYLELVKSL LOC642502, SDHC 154845.doc • 11 - 201200594 50 PBK-001 SYQKVIELF PBK 51 POLD3-001 LYLENIDEF POLD3 52 PSMD14-001 VYISSLALL PSMD14 53 PTK2-001 RYLPKGFLNQF PTK2 54 RPS11- 001 YYKNIGLGF RPS11 55 TSPAN1-002 VYTTMAEHF TSPAN 1 56 ZNF598-001 DYAYLREHF ZNF598 57 ADAM 10-001 LYIQTDHLFF ADAM 10 58 MMP12-001 TYKYVDINTF MMP 12 59 RRM2-001 YFISHVLAF RRM2 60 TMPRSS4-001 VYTKVSAYL TMPRSS4 61 TSPAN8-001 VYKETCISF TSPAN8 The invention In another embodiment, an HLA A*02 binding peptide directed against gastric cancer is disclosed. For A*02 and/or A*24 positive populations, a mixture of the disclosed peptides can be used to treat gastric cancer. Preferably 2 to 20 peptides and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 peptides a mixture. SEQ ID NO: Peptide code sequence source protein 62 DI02-001 ALYDSVILL DI02 63 IGF2BP3-001 KIQEILTQV IGF2BP3 64 LMNB1-001 LADETLLKV LMNB1 65 WNT5A-001 AMSSKFFLV WNT5A 66 FAP-003 YVYQNNIYL FAP 67 COPG-OOl VLEDLEVTV COPG, COPG2, TSGA13 68 COL6A3-002 FLLDGSANV COL6A3 69 COL6A3-003 NLLDLDYEL COL6A3 70 COL6A3-004 FLIDSSEGV COL6A3 71 PSMC2-001 ALDEGDIAL PSMC2 72 UBE2S-001 ALNEEAGRLLL UBE2S 73 KIF11-001 ILSPTVVSI KIF 11 154845.doc -28 - 8 201200594

74 ADAM8-001 KLLTEVHAA ADAM8 75 CCNB1-001 ALVQDLAKA CCNB1 76 CDC6-001 ILQDRLNQV CDC6 77 F2R-001 TLDPRSFLL F2R 78 OLFM4-001 TLDDLLLYI OLFM4 79 THY1-001 SLLAQNTSWLL THY1 80 CEP250-001 SLAEVNTQL CEP250 81 HIF1A-001 ALDGFVMVL HIF1A 82 KRAS -001 GVDDAFYTL KRAS 83 MET-001 YVDPVITSI MET 84 NCAPG-001 YLLSYIQSI NCAPG 85 NCAPG-002 QIDDVTIKI NCAPG 86 TOP-004 YLYGQTTTYL TOP2A 87 TOP-005 KLDETGNSL TOP2A 88 LAMC2-002 RLDDLKMTV LAMC2 89 AHR-001 LTDEILTYV AHR 90 CCNB1-002 ILIDWLVQV CCNB1 91 CEACAM6- VLYGPDVPTI CEACAM6 001 92 COPB1-001 SIFGEDALANV COPB1 93 HMMR-001 KLLEYIEEI HMMR 94 TPX2-001 KILEDVVGV TPX2 95 KIFDEILVNA TOP2A, TOP-001 TOP2B Cell division cycle 2 protein (CDC2) Serine/threonine kinase CDC2 is also known as Cdk1 (cyclin-dependent kinase 1), which plays a key role in cell cycle control. It is known to be the major regulator of G2 to Μ conversion. At the end of the interval, it binds to type A cyclins. After nuclear membrane rupture, type A cyclins are replaced by cyclin B, which forms a mitotic promoting factor (MPF) with Cdc2. MPF is important for driving cells to complete mitosis to 154845.doc -29- 201200594.

The function of Cdc2 in mitosis is not superfluous and cannot be compensated for by the activity of other cdk such as Cdk2, Cdk4 and Cdk6. Conversely, it has also been reported that Cdc2 plays a role in other phases of the cell cycle, such as 〇 1 _s conversion, and it can replace “interphase Cdk”. Therefore, Cdc2 is considered to be the only essential cell cycle Cdk » In several cancers, Cdc2 overexpression is often associated with poor prognosis. These cancers are prostate cancer, oral cancer, oral squamous cell carcinoma (OSCC), Acute myeloid leukemia (AML) (Qian et al.), MALT lymphoma caused by Helicobacter pylori (Banerjee et al., 217-25), and colon cancer (Yasui et al., 36-41^ in gastric cancer have been reported to be overdose) Increased performance and/or activity' and may play a role in pathogenesis. Inhibitors of Cdc2 and other Cdk are also considered candidates for cancer therapy (Shapir〇177〇_83). Abnormal Spindle Microcephaly Related Proteins ( ASPM) Abnormal spindle-shaped microcephaly-associated protein (ASPM) is a human orthologous gene of the fruit spindle abnormal spindle (asp), which is involved in the regulation of neuronal production, and the mutation causes the chromosome to be recessive primary microcephaly^ ASPM is located at both ends of the spindle during mitosis. ASPM overexpression is suggested as a marker for glioblastoma and a potential therapeutic target. siRNA-mediated blockade of gene expression inhibits tumor cell proliferation and nerves Cell proliferation. Aspm overexpression can also predict increased aggressiveness/metastasis of hepatocellular carcinoma, early tumor recurrence, and poor prognosis. ASPM is up-regulated in both immortalized and non-small cell lung cancer tissues (Jung, Choi, and Kim 703- 13). Matrix metalloproteinase 3 (MMP3) 154845.doc -3〇- 8 201200594 MMP3 is also known as gelatinase or matrix degrading factor 1, which is a component of degrading extracellular matrix (ECM) (such as fibronectin, Endopeptidases of laminin, elastin, proteogical core protein, and collagen non-helical regions. MMPs are important for several physiological processes that require ECM rearrangement, such as embryonic development, tissue remodeling, and blood vessels. Cell migration during formation, lactation, and wound healing. MMP3 also plays a role in platelet aggregation. Pathological conditions involving enhanced expression and secretion of the river ^11>3 include autoimmune inflammatory conditions and cancer. Excessive manifestations in certain tumors and play a role in epithelial-mesenchymal transition (EMT). They may also be involved in early steps of carcinogenesis, triggering extragenic It leads to a malignant phenotype (Lochter et al., 180_93). Polymorphisms in the MMP3 promoter associated with performance indicate an impact on the risk and prognosis of certain cancers, such as esophageal adenocarcinoma (Bradbury et al., 793_) 98) and oral squamous cell carcinoma (Vairaktaris et al., 4〇951〇〇乂 et al., 430-35). Patients with Helicobacter pylori-positive gastric cancer with elevated serum levels of MMP3 and MMP7 showed higher lymph node invasion and Short life span. Of a group of 74 patients with gastric cancer, 27% had MMp3 performance (Murray et al., 791-97). c-Met c-Met mediates the potential carcinogenic activity of hepatocyte growth factor (HGF)/dispersion factors, including promoting cell growth, exercise, survival, extracellular matrix lysis, and blood moss production. Binding of HGF activates downstream signaling events, including Ras, phospholipid creatinine 3'-kinase, phospholipase, and mitogen-activated protein-excited S#-related pathways (Dong, 5911-18; Furge et al., 10722-27) ; 154845.doc 201200594

Furge, Zhang, and Vande Woude 5582-89; Montesano et al., 355-65; Naldini et al., 501-04; Ponzetto et al., 4600-08). c-Met is mainly expressed in epithelial cells. The oncogenic activation of c-Met (also in non-epithelial malignant tissue) can be caused by amplification/overexpression, activating mutations, obtaining HGF/c-Met autocrine loops or constitutive phosphorylation (Di Renzo et al., 147- 54; Ferracini et al, 739-49; Fischer et al, 733-39; Koochekpour et al, 5391-98; Li et al, 8125-35; Maulik et al, 41-59; Qian et al, 589-96; Ramirez et al., 635-44; Tuck et al., 225-32) (Nakaigawa et al., 3699-705). C-Met constitutive activation in transgenic mice with excessive HGF expression promotes extensive tumor formation (Takayama et al., 701-06; Wang et al., 1023-34^ MET silencing inhibits tumor growth and metastasis (Corso et al., 684-93). Amplification of MET is associated with progression of human gastric cancer (Lin et al., 5680-89) (Yokozaki, Yasui, and Tahara 49-95). Ubiquitin carboxy terminal hydrolase L5 (UCHL5) UCHL5, also known as ubiquitin C-terminal hydrolase (UCH37) or INO80R, is a proteasome-associated deubiquitinase that cleaves an isopeptide bond between C-terminal Cys76 and Lys48. The linked polyubiquitin chain is separated from the distal end (Nishio et al., 855-60). In the nucleus, UCHL5 binds to the Ino80 chromatin remodeling complex. When bound to the proteasome, it is activated and may be involved in transcription. Regulation or DNA repair, which is suggested to be mediated by Ino80 and proteasome. Ubiquitin-specific proteases (such as UCHL5) are involved in such factors as cell cycle progression control, differentiation, DNA replication and repair, transcription, protein quality control, 154845.doc - 32- 8 201200594 Immune Response and Apoptosis Several processes ^ UCHL5 may promote malignant transformation. It has been shown to be up-regulated in human cervical cancer tissue compared to adjacent normal tissues. It can be deubiquitinated, thereby making TGF-β receptor and its downstream regulatory factors Smad is stable and thereby enhances TGF-β signaling. Although TGF-β彳§ conduction has dual functions and acts as a tumor suppressor early and early in cancer, enhanced TGF-β signaling can be used in advanced cancer progression. Tumor promoters (Bierie and Moses 29-40; Horton et al., 138-43; Wicks et al., 8080-84; Wicks et al., 761-63). Macrophage stimulating protein receptor (MST1R) MST1R (alias R 〇N) The receptor is a member of the cell surface receptor tyrosine kinase Met family and is mainly expressed on epithelial cells and macrophages. MST1R can induce cell migration, invasion, proliferation and survival by reacting with its ligand. It has been shown to be carcinogenic in vitro and in animal models and is downregulated in human cancers (Dussault and Bellon, 2009). Clinical studies have shown that MST1R overexpression is associated with poor prognosis and metastasis. MST1R Significant manifestations in gastric cancer tissues and corresponding paraneoplastic tissues, but not observed in normal monthly mucosa (Zhou et al., 236-40). Blocking] VIST1R in prostate cancer cells can induce endothelial cell chemotaxis in vitro The effect is reduced, and tumor growth and microvessel density are reduced after orthotopic transplantation into the prostate. Blocking of siRNA-mediated MST1R expression in highly tumorigenic colon cancer cell lines resulted in reduced proliferation compared to control cells. Kinesin-like protein (KIF2C) KIF2C is a microtubule depolymerase that regulates proper kinetochore-microtubule junctions during spindle formation. It is important for late chromosome segregation and may require 154845.doc •33· 201200594 to coordinate sister centromere separation. Microtubule junctions that interfere with kinetochore in many solid tumors can lead to chromosomal mis-segregation and aneuploidy (Maney et al., 67-131; Moore and Wordeman 537-46). KIF2C is overexpressed in breast cancer cells (Shimo et al., 62-70), colon cancer, colorectal cancer, and gastric cancer (Nakamura et al., 543-49). The gastric cancer cell line (AZ521) stably expressing KIF2C showed an increase in proliferation and migration compared to the mock-transfected cells. Increased expression of KIF2C in gastric cancer may be associated with lymphatic invasion, lymph node metastasis, and poor prognosis. Treatment of breast cancer cells with small interfering RNA against KIF2C inhibits the growth of breast cancer cells. Chromosome Structure Maintenance Protein 4 (SMC4) The SMC protein is a chromosomal ATPase that functions in high-level chromosome organization and kinetics. SMC4 is a core component of the agglomerated protein complex, which plays a role in chromatin condensation and is also involved in the separation of nucleoli, DNA repair, and maintenance of chromatin scaffolds. The SMC4 gene is known to be highly expressed in normal prostate and salivary glands, is extremely weak in the colon, pancreas, and intestine, and does not manifest at all in other tissues. High RNA expression was observed in many cancer cell lines and cancer samples, including breast cancer, prostate cancer, colon cancer, and pancreatic cancer (Egland et al., 5929-34).

Ephrin A receptor 2 (EPAH2)

The Eph receptor is a unique family of receptor tyrosine kinases (RTKs) that play a key role in embryonic pattern establishment, neuronal targeting, and vascular development during normal embryogenesis. Stimulation of EphA2 with its ligand (ephrin-Al) results in Eph A2 self-priming acidification, which reverses oncogenic transformation. The Eph receptor and its ligand ephrin are often overexpressed in a variety of cancers. EphA2 154845.doc .34- 201200594 is often overexpressed and functionally altered in invasive tumor cells and is thought to be promoted by enhancing cell-extracellular matrix adhesion, anchorage-dependent growth, and angiogenesis. Tumor growth. Excessive expression of EphA2 and EphrinA-Ι is shown in gastric cancer, which is associated with tumor invasion depth, tumor lymph node metastasis (TNM) stage, lymph node metastasis, and poor prognosis (Yuan et al., 2410-17). ATAD2 ATAD2 (also known as ANCCA) is a new member of the AAA+ ATPase family of proteins. It enhances the transcriptional activities of androgen receptor (AR) and estrogen receptor (ER), including IGF1R, IRS-2, SGK1 and survivin (AR) and cyclin D1, c-myc and E2F1 (ER, respectively). ) Gene transcription. It also enhances the transcriptional activity of c-Myc. ATAD2 is shown to be higher in several human tumors such as breast cancer, prostate cancer and osteosarcoma. Its performance is associated with poor prognosis. AVL9 unexpectedly found this protein to be a source protein, and there is little and very limited information on the function of the AVL9 protein and its corresponding genes. Collagen alpha-Ι (ΧΙΙ) chain protein (Co丨12A1) The collagen alpha-Ι (ΧΙΙ) chain is a protein encoded by the COL12A1 gene in humans. This gene encodes the alpha chain of type XII collagen, which is a member of the collagen family of FACIT (a fibril-associated collagen protein of discrete triple helix). XII type collagen was found to bind to type I collagen homologous trimers, and this binding was thought to modify the interaction between collagen I fibrils and the surrounding matrix. It has been identified that it can be encoded 154845.doc •35· 201200594 Alternative mosaic transcript variants of different isoforms. Ketogenin a-3(VI) chain protein (COL6A3) COL6A3 encodes one of the three alpha bonds of alpha-3 bond, the type VI collagen. This protein domain has been shown to bind to extracellular matrix proteins, which indicates the importance of this collagen in tissue matrix components. Beta is embedded in cancer cells, and is reconstituted outside the cell via excess expression of collagen. The matrix contributes to cisplatin resistance. The presence of collagen V is associated with tumor grade, a prognostic factor for ovarian cancer (Sherman-Baust et al, 377-86). COL6A3 is overexpressed in colorectal tumors (smith et al, 1452-64), salivary gland cancer (Leivo et al, 104-13) and is differentially expressed in gastric cancer (Yang et al, 103 3-40). c〇L6 A3 has been identified as one of the seven genes with tumor-specific splicing variants. Tumor-specific splicing changes have been demonstrated to be highly consistent, so that normal samples and cancer samples can be clearly distinguished and, in some cases, even different tumor stages can be distinguished (Th〇rsen et al., 1214-24). Fanconi Anemia Complement I (FANCI) FANCI protein is mapped to chromatin and participates in DNA repair in response to DNA damage (Sm〇gorzewska et al., 289_3〇1). FANCw causes mutations in Fanconi due to mutations, a recessive genetic heterogeneity characterized by cytogenetic instability, allergic to cross-linking agents, increased chromosome breaks, and defects in DNA repair. Alternative splicing of FANCI forms two transcript variants encoding different isoforms. Heat shock protein 90 kDap member 1 (HSP90B1) HSP90 (also known as glucose regulatory protein 94, Grp94) member i is a 154845.doc -36-201200594 human chaperone protein. It participates in er-related processes: translation, protein quality control and ER-related degradation (EraD), ER stress perception, and ER binding/fishing retention (Christianson et al., 272-82; Fu and Lee 741·44). HSP90 contains the KDEL sequence typical of ER-retained proteins, but it also appears on the surface of tumor cells (Altmeyer et al., 340-49) as well as extracellular. HSP is known to be released from necrotic (but not apoptotic) cells and cells under pressure from various stimuli such as heat shock and oxidative stress, and can occur in the circulation (Basu et al., 1539-46; Tsan and Gao 274). -79). In vitro, HSP90 regulates (primarily stimulates) the immune response and participates in antigen presentation. On the cell surface, it acts as a receptor for pathogen entry and/or signaling (Cabanes et al., 2827-38). It can induce anti-tumor immunity in the presence or release of tumor-specific cell surface (Zheng et al., 6731-35). In both prophylactic and therapeutic regimens, hSP9-based vaccines have been shown to be immune to cancer and infectious diseases (reviewed in (B〇lhassani and Rafati Π85-99; Castelli et al., 227-33; Murshid, Gong, And Calderwood 1019-30)). However, 'HSP90 can also be considered as a target for tumor therapy because it is associated with tumor progression and also causes resistance to apoptosis after irradiation or chemotherapy, and 2) it is overexpressed in many tumors, including Osteosarcoma (Guo et al '62-67), breast cancer (H〇d〇r〇va et al, 31_35). Excessive performance of HSP90 is associated with aggressive behavior and poor prognosis of Gc (Wang, Wang, and Ying 35-41; Zheng et al., 1042-49). Down-regulation of HSP90 in the GC can cause apoptosis in cancer cells (at (3), Liu, and Lan el096). 154845.doc -37- 201200594

Muc 6 MUC6 is expressed in mucus cells. Its primary function is believed to protect the vulnerable epithelial surface from the devastating effects of continuous exposure to a variety of endogenous corrosives or proteolytic agents (T〇ribara et al., 1 997). MUC6 also plays a role in epithelial organ formation (Reid and Harris, 1999). It was found that MUC6 behaves in normal gastric adhesion. It is overexpressed in some cancers, such as intestinal adenoma and intestinal cancer, lung cancer (Hamamoto et al '891-96), reclamation polyps (Bartman et al, 210-18) and breast cancer (pereira et al, 21〇_ 13) 'Not in the normal organization. Due to the high rate of expression of muc6 in mucinous carcinoma, it has been suggested as a barrier to cancer spread, leading to a decrease in the aggressiveness of its biological behavior (Matsukita et al., 26-36). The performance of MUC6 in gastric cancer is lower than that in adenoma or normal mucosa, and is negatively correlated with tumor size, depth of invasion, lymphatic and venous invasion, lymph node metastasis and UICC staging. MUC6t modulation promotes the malignant transformation of gastric epithelial cells and becomes the molecular basis for growth, invasion, metastasis and differentiation of gastric cancer (Zheng et al., 817-23). There is also evidence that H. pylori infection (one of the main causes of gastric cancer) is associated with decreased MUC6 performance (Kang et al., 29_35; Wang and Fang 425-3 1). The kineoglobulin Nuf2 NUF2 (CDCA-1) gene encodes a protein that is highly similar to yeast Nuf2, a component of a conserved protein complex associated with centromeres. In the pre-meiosis stage, when the centromere is disconnected from the spindle body, the yeast Nuf2 disappears from the centromere and plays a regulatory role in chromosome segregation. Studies have shown that survivin and hNuf2 csiRNA temporarily block their mRNA expression, • 38 - 154845.doc

201200594 causes multinucleation and cell death via blockade of mitosis, respectively (Nguyen et al., 394-403). Nuf2 and Heel are required to stabilize the microtubule positive-end binding site in the outer plate, which is required for the continuous polar force required for biaxial orientation at the kinetochore (DeLuca et al., 519-31). The study found that Nuf2 protein is overexpressed in NSCLC (associated with poor prognosis) (Hayama et al., 10339-48) and cervical cancer (Martin et al., 333_59). In the surgically resected gastric cancer tissue (diffuse type, 6; intestinal type, 4), the two NUF2 variants were up-regulated. Alternative splicing variants detected in this study have been suggested to be useful as diagnostic markers for anticancer therapy and/or new lysate (Ohnuma et al., 57-68). siRNA-mediated blockade of NUF2 has been found to inhibit cell proliferation and induce N-cells in NSCLc, ovarian, cervical, gastric, colorectal, and gliomas; weekly death (Kaneko et al., 1235- 40). Lipid sulphate reductase 2 (PPAP2C) canola acid phosphatase (PAP) converts phosphatidic acid to dimercaptoglycerol, and in the re-synthesis of glycerol lipids and in phospholipase D-mediated receptor activation The guide plays a role. It has been reported that it has three alternative splicing transcript variants encoding different isoforms. ? ?八1>2(:; is upregulated in transformed primary adult mesenchymal stem cells (MSC) and many human cancers. It may be required for increased cell proliferation. Excessive performance of PPAP2C (but not catalytically inactive mutants) leads to Premature entry into S phase, accompanied by accumulation of premature cyclin a. Blocking its gene expression can reduce cell proliferation by delaying entry into S phase (Fianagan et al., 249-60). 40S ribose Zhao protein sil is a protein (Rpsii) I54845.doc •39- 201200594 The ribose system consists of a small 40S subunit and a large 60S subunit. The subunits are composed of 4 RNAs and about 80 different structural proteins. The RPS11 gene is encoded as 40S. Subunit component ribosomal protein. RPS11 is one of the six genes that have been found to be useful for screening fecal RNA-based markers for the diagnosis of colorectal cancer, especially in fecal colon cells derived from cancer patients. Found (Yajima et al., 1029-37). E3 ubiquitin ligase seven absttia homolog 2 (SIAH2) SIAH2 is E3 ubiquitin ligase. Its receptor is β-catenin, TRAF2 and DCC. (knot Deletion in rectal cancer) (Habelhah et al., 5756-65; Hu and Fearon 724-32; Nakayama, Qi, and Ronai 443-51). SIAH2 also causes degradation of nuclear protein repp86, resulting in mitosis induced by excessive protein expression. Block elimination (Szczepanowski et al., 485-90). SIAH2 has tumor and metastasis-promoting properties via at least two pathways (see Nakayama, Qi, and Ronai 443-51): first, it causes in the hypoxic response pathway The ubiquitination and degradation of proteins enhances the transcriptional activity of hypoxia-inducible factor (HIF) (Nakayama, Qi, and Ronai 443-51) (Calzado et al., 85-91). Second, it inhibits Ras/ERK. Sprouty2, a specific inhibitor of signaling. SI AH2 activity may be associated with the development of pancreatic tumors via its positive effects on Ras signaling (Nakayama, Qi, and Ronai 443-51). Although SIAH2 plays a role in cancer. Partial controversy, but some reports indicate that low levels of SIAH2 are associated with poor prognosis or treatment response (Confalonieri et al., 2959-68) (Jansen et al., 263-71), and other reports have shown tumorigenic function (Frasor et al) , 13153-57). SIAH2 154845.doc •40· 201200594 Inhibition has been considered an anti-cancer treatment because it has been shown to inhibit xenograft growth in a melanoma mouse model (Qi et al., 16713-18; Shah Et al., 799-808) and inhibition of growth of human lung cancer cell lines transplanted into nude mice (Ahmed et al., 1606-29). Sodium and Gas Dependent Taurine Transporter (SLC6A6) SLC6A6 is a sodium and chlorine dependent taurine transporter (TauT) (Han et al., 2006). Taurine transporter knockout (taut-/-) mice suffer from chronic liver disease due to the lack of taurine, which may be involved in mitochondrial dysfunction (Warskulat et al., 2006). The expression of SLC6A6 is suppressed by the p53 tumor suppressor gene and is deactivated by protooncogenes such as WT1, c-Jun and c-Myb. Excessive expression of SLC6A6 protects kidney cells from cisplatin-induced nephrotoxicity (Han et al, 2006; Han and Chesney, 2009). In human intestinal epithelial Caco-2 cells, SLC6A6imRNA is up-regulated by tumor necrosis factor a (TNF-a). Ubiquinol-cytochrome c reductase binding protein (UQCRB) The protein encoded by the UQCRB gene is part of the Ubiquinol-cytochrome c oxidoreductase complex. It combines with ubiquinone and participates in electron transfer. Mutations in this gene are associated with a lack of mitochondrial complex III. It has been documented that there are pseudogenes on the X chromosome. The UQCRB gene may be a potential oncogene or tumor suppressor gene in pancreatic ductal adenocarcinoma (Harada et al., 13-24). It has been found to be overexpressed in hepatocellular carcinoma (Jia et al., 1 133-39). Human epidermal growth factor receptor 3 (ERBB3) ERBB3 encodes a receptor for tyrosine kinase epidermal growth factor receptor (EGFR) home 154845.doc -41 - 201200594 One of the members. It is activated by neuregulin, other ERBB receptors and non-ERBB receptors as well as other kinases and is activated by novel mechanisms. Downstream, it interacts primarily with the phosphoinositide 3-kinase/AKT survival/mitogenic pathway and also interacts with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcriptional regulator EBP1 (Sithanandam and Anderson 413-48) ). Overexpression of ERBB3 has been found in many cancers, including gastric cancer, where it may play a key pathogenic role and negatively affect prognosis (Kobayashi et al, 1294-301) (Slesak et al, 2727-32). (Zhang et al., 2112-18) found that ERBB3 overexpression was more frequent in diffuse gastric cancer (26.2%) than in intestinal type gastric cancer (5.0%). In both types, overexpression was associated with poor prognosis. Methods for targeting ERBB3 in cancer therapy include RNA aptamers directed against the extracellular domain (Chen et al., 9226-31), blocking their gene expression using synthetic transcription factors (Lund et al., 9082-91), such as vitamin E Small molecule inhibitors of the gamma-diene tocopherols (gamant and §ylvester 563-74), miRNA (Scott et al., 1479-86) and siRNA (Sithanandam et al., 1847-59).

Prominin l (Proml) Function: Prominin-1, also known as CD133, is identified as a molecule specific for CD34+ progenitor cells (Yin et al., 1997) and has been shown to be normal stem cells and cancer stem cells of various tissues. (CSC) marker. It is mainly located in the prominent part of the plasma membrane and may be involved in the organization of the membrane topology or maintain the lipid composition of the plasma membrane. The prominind splicing isomer, known as AC133-2 and lacking a small exon with 27 amino acids, is believed to represent a better stem cell marker (Mizrak et al., 2008; Bidlingmaier et al. 154845.doc ^ 8 201200594 , 2008). Only a small percentage of tumor cells are usually positive for prominin-1, as can be expected with CSC markers. Depending on the type of tumor, the number of positive cells per tumor block is between 1% and 15%, and most is around 2%.

Prominin-Ι is associated with tumor formation, angiogenesis, and chemoresistance (Zhu et al, 2009a) (Bruno et al, 2006; Hilbe et al, 2004) (Bertolini et al, 2009). However, since prominin-Ι positive cells may be killed by NK cells (Castriconi et al., 2007; Pietra et al., 2009) and cytotoxic T cells (Brown et al., 2009), they may be invaded by the immune system. Although prominin-1 positive cells have been shown to be functionally CSC in many cancer entities and their performance is often associated with poor prognosis, it remains controversial. Some reports indicate that it is not necessarily or insufficient to determine CSC (Cheng et al., 2009; Wu and Wu, 2009), perhaps a combination of prominin-1 with other molecules such as CD44, or even with proml(+), Multiple combinations of CD34(+), CD44(+), CD3 8(-), CD24(-) can serve as preferred CSC markers (Zhu et al., 2009b; Fulda and Pervaiz, 2010) ° in diffuse GC, The presence of PROM1 was presumed based on electronic hybridization analysis (Katoh and Katoh, 2007), and (Smith et al., 2008) reported overexpression in GC compared to normal gastric tissue protein content. However, (Boegl and Prinz, 2009) reported that prominin-Ι expression was reduced in the GC, especially in the later stages, and that prominin-1 expression was associated with angiogenesis (and decreased in the later stages), but not with tumor growth. A study using GC cell lines (Takaishi et al., 2009) concluded that CD44 is a CSC marker for GC, 154845.doc -43-201200594 and prominin-l is not. Matrix Metalloproteinase 11 (MMP11) Like other MMPs, MMP11 is also an endopeptidase that plays a role in tissue remodeling processes such as development, wound healing and scar formation. It also negatively regulates fat by reducing fat cell differentiation. In contrast to other MMPs, it does not cleave typical extracellular matrix molecules other than collagen. However, other receptors for ΜΜΡ11 have been identified, such as α2_ macroglobulin, certain serpin inhibitors (including α1 antitrypsin), insulin-like growth factor binding protein 1 and laminin receptors. In cancer, MMP 11 is predominantly expressed in stromal cells surrounding tumor tissue. It has been demonstrated in many tumor entities. ΜΜΡ11 is thought to be overexpressed in the matrix of most invasive human carcinomas, but rarely in sarcomas and other non-epithelial tumors. In most, but not all cases, ΜΜΡ11 is expressed in stromal cells directly adjacent to the tumor, while the tumor cells themselves, normal tissues, and stromal cells distant from the tumor are negative. Higher MMP 11 levels are associated with a malignant phenotype/higher invasiveness and poor prognosis. However, in papillary thyroid cancer, ΜΜΡ11 performance is inversely associated with aggressive characteristics. MMP 11 was found in tumor tissues as well as in gastric cancer patients, and its expression was associated with metastasis (Yang et al.). Furthermore, (Deng et al., 274-81) studies have shown that 'MMP11 is highly expressed in gastric cancer cell lines and primary tumors', which is not only expressed in the matrix, but is contrary to the performance of other cancer types, and It seems to enhance tumor cell proliferation. Nuclear transcription factor Y-subunit P (NFYB) NFYB is also known as CBF-B or CBF-A, which is a NFYC exo-trimer based transcription factor NF-Υ (also known as NFYA and 154845.doc 8 201200594 NFYC) Part of the CCAAT binding factor or CBF), which binds to the CCAAT motif in many gene promoters and enhancers (or the reverse motif ATTGG called the Y cassette). The NF-Υ target gene includes an MHC class II gene, a PDGFP receptor, several heat shock proteins, a mismatch repair gene hMLH1, and a topoisomerase ΙΙα. NFYB is not a traditional oncogene, but its function may promote tumor formation. First, many cell cycle genes such as cyclin A, cyclin B1, Aurora kinase A, and cdkl are targets of NF-Υ. The blockade of cells in the G2/M phase does not require functional NFYB. (Park et al.) Studies have shown that cyclin B2 and other cell cycle-associated genes are upregulated by NF-Υ activity in colorectal adenocarcinoma. Second, the activity of NF-Υ inhibits apoptosis. Cells lacking NF-Υ are apoptotic due to p53 activation and decreased transcription of anti-apoptotic genes (such as Bcl-2) containing the CCAAT box in the promoter (Benatti et al., 1415-28). Third, its tumorigenicity is enhanced when combined with other transcription factors. For example, binding of mutated p53 to NF-Υ and p300 proteins increases the expression of NF-Υ-induced cell cycle genes. The ABL1 protein tyrosine kinase c-Abl shuttles between the nucleus and the cytoplasmic compartment. Nuclear c-Abl is involved in cell growth inhibition and apoptosis, while cytoplasmic c-Abl may be involved in actin dynamics, morphogenesis, and signaling induced by extracellular stimuli such as growth factors and integrin ligands. Play a role. It has been reported that cytoplasmic c-Abl promotes mitogenesis. The activity of the c-Abl protein is negatively regulated via its SH3 domain, and deletion of the SH3 domain causes ABL1 to become an oncogene. In chronic myelogenous leukemia (CML), the 154845.doc -45-201200594 gene is activated by displacement within the BCR (crack point cluster) on chromosome 22. The resulting fusion protein BCR-ABL is located in the cytosol and allows the cells to proliferate without cytokine regulation (Zhao et al.). c-Abl activity is also up-regulated in solid tumors, as in breast cancer and NSCLC. Excessive performance is not sufficient and protein kinase activity requires protein phosphorylation. In breast cancer cells, c-Abl phosphorylation is induced by cytoplasmic membrane tyrosine kinases, including SFK, EGFR family members, and IGF-1 receptors. ABL fusion proteins have not been detected in solid tumors (Lin and Arlinghaus, 2008). ABL is shown to be expressed in gastric cancer and is associated with microvasculature, suggesting that it may play a role in angiogenesis. Notably, H. pylori cytotoxin associated gene A (CagA) activates c-Abl, thereby phosphorylating EGFR, thereby blocking EGFR endocytosis (Bauer, Bartfeld, and Meyer 1 56-69). Several statin kinase inhibitors are somewhat specific for Abl. Imatinib (Gleevec) is used as a line therapy for CML and because it also targets KIT, it is also licensed for patients with advanced gastrointestinal stromal tumors (GIST) (Pytel et al., 66-76). (Croom and Perry, 2003). Other inhibitors for cancer therapy are Dasatinib and Nilotinib (Pytel et al., 66-76) (Deremer, Ustun, and Natarajan 1956-75).

Polo-like kinase 4 (Plk4)

Members of the Polo kinase family (Plkl to Plk4) are important in cell division, which regulates several steps in the process of mitosis. Plk4 is the organizer of the formation and replication of centrosomes (Rodrigues-Martins et al., 1046-50). Although Plkl is a well-defined oncogene, the function of Plk4 in cancer is not yet clear. Down-regulation of Plk4 and overexpression are associated with cancer in humans, mice and flies 154845.doc -46-^ 8 201200594 (Cunha-Ferreira et al., 43-49). For example, in colorectal cancer, Plk4 was found to be overexpressed, but a small percentage of patients showed a strong down-regulation of Plk4 (Macmillan et al., 729-40). This phenomenon can be explained by the fact that excessive expression and deficiency of Plk4 leads to the formation of abnormal centrosomes, thus resulting in the number and structure of abnormal centrosomes, which are often detected in tumor cells and promote mitosis. Distortion, causing chromosome segregation and aneuploidy (Peel et al., 834-43). (Kuriyama et al., 2014-23). (Korzeniewski et al., 6668-75). IQ-containing GTPase-activating protein 3 (IQGAP3) IQGAP is involved in cell signaling pathways as well as cytoskeletal structure and cell adhesion. It has a domain similar in sequence to RasGAP and thus binds to a small GTPase. However, although they have such a name, none of them has GTPase activating activity. For IQGAP1 and IQGAP2, it has been shown that it even stabilizes the GTP binding status of Racl and Cdc42, and shows that IQGAP3 stabilizes activated Ras (Nojima et al., 971-78; White, Brown, and Sacks 1817-24). Through its IQ domain, it binds to calcium/calcium-regulated proteins and binds to actin filaments via a calcium regulatory protein homology domain (White, Brown, and Sacks 1817-24). (Wang et al., 567-77) Studies have shown that IQGAP3 is expressed in the brain and binds to wit actin filaments and Racl and Cdc42 in the brain. It accumulates in the distal region of the axon and promotes Racl/Ccd42-dependent axon growth. IQGAP is associated with cancer. IQGAP1 is considered an oncogene. It enhances several cancer-related pathways such as MAP kinase, β-catenin and VEGF-mediated signaling, and is overexpressed in many tumors. IQGAP2 appears to play a role in tumor suppressor 154845.doc -47- 201200594 and was found to be reduced in poor prognosis of gastric cancer (White, Brown, and Sacks 1817-24). Little information is available about IQGAP3. (Skawran et al., 505-16) was found to be one of the genes that are significantly up-regulated in hepatocellular carcinoma. Two studies indicated that IQGAP3 is specifically expressed in proliferating (Ki67 + ) cells in the small intestine, colon and liver of mice (Nojima et al., 971-78) (Kunimoto et al., 621-31). The coiled-coil domain 88a (CCDC88A) CCDC88A is an actin-binding Akt receptor that functions in actin tissue and Akt-dependent cell movement in fibroblasts. The CCDC88A/Akt pathway is also required for VEGF-mediated neovascularization. CCDC88A is also highly expressed in a variety of human malignant tissues, including breast cancer, colon cancer, lung cancer and cervical cancer. It plays an important role in the progression of tumors with abnormal activation of the Akt signaling pathway. Cyclin B1 (CCNB1) CCNB 1 is induced in the G2/M phase of mitosis and forms a mitogenic factor (MPF) together with the cell cycle protein-dependent kinase 1 (Cdkl)/Cdc2. Overexpression has been found in a variety of cancers and is often associated with poor prognosis, such as breast cancer (Aaltonen et al, 2009; Agarwal et al, 2009; Suzuki et al, 2007), blastocytoma (de et al, 2008). ), NSCLC (Cooper et al, 2009), cervical cancer (Zhao et al, 2006) and other cancers. It was found to predict one of the genes included in the 11 gene signature for short-spatial disease recurrence in 12 different types of cancer patients. No specific information about gastric cancer was found. 154845.doc -48 · 8 201200594 Cyclin D2 (CCND2) Similar to other D-type cyclins (D1 and D3), CCND2 binds to and activates cyclin-dependent kinase 4 (Cdk4) or Cdk6. This activity is required for G1/S conversion. CCND2 has been found to be overexpressed in many tumors, including testicular and ovarian tumors (Sicinski et al., 1996), hematologic malignancies (Hoglund et al., 1996; Gesk et al., 2006), and gastric cancer, which may be infected by H. pylori. Caused by, and associated with poor prognosis (Yu et al, 2003). (Yu et al. 2001) (Oshimo et al., 2003) (Takano et al., 1999) (Takano et al., 2000). Cyclin E2 (CCNE2) is similar to another E-type cyclin CCNE1, which binds to and activates Cdk2. This activity peaks during the G1/S phase transition. Under healthy conditions, CCNE2 is not detected in resting cells and can only be found in active dividing tissues (Payton and Coats, 2002). It is usually abnormal in cancer, such as breast cancer (Desmedt et al, 2006; Ghayad et al, 2009; Payton et al, 2002; Sieuwerts et al, 2006) and metastatic prostate cancer (Wu et al, 2009), And related to poor prognosis. Cancer Embryonic Antigen-Related Cell Adhesion Molecules 1, 5 and 6 (CEACAM 1, 5 and 6) CEACAM is a membrane-anchored glycoprotein that mediates cell-cell interactions and activates the integrin signaling pathway (Chan and Stanners, 2007) . It can also act as a receptor for pathogens such as E. coli (Berger et al., 2004) (Hauck et al., 2006) and can participate in immunomodulation (Shao et al., 2006) ° 154845.doc -49- 201200594 CEACAM5 and CEACAM6 Has a cancer-promoting function. It inhibits anoikis apoptosis (Ordonez et al., 2000), promotes metastasis (Marshall, 2003; Ordonez et al., 2000) and disrupts cell polarization and tissue architecture (Chan and Stanners, 2007). The role of CEACAM1 in cancer is unclear. It may be an early tumor suppressor and promotes late metastasis formation, tumor immune escape and angiogenesis (Hokari et al, 2007; Liu et al, 2007; Moh and Shen, 2009). Its functional role depends on its isoforms, as CEACAM1 appears in 11 splicing variants, and the ratio of these splicing variants determines signal transduction results (Gray-Owen and Blumberg, 2006; Leung et al., 2006; Neumaier Et al., 1993; Nittka et al., 2008). The ratio of splicing variants can vary in cancer (Gaur et al., 2008). CEACAM5 or CEACAM6 or both are overexpressed in up to 70% of all human tumors, which are often associated with poor prognosis (Chan and Stanners, 2007; Chevinsky, 1991). Serum CEACAM5 is a clinical marker of established colon and rectal cancer, with high levels indicating poor prognosis or recurrence (Chevinsky, 1991; Goldstein and Mitchell, 2005). It is also considered to be a marker for other entities, including gastric cancer, however, the ability to predict prognosis is limited (Victorzon et al., 1995). CEACAM1 can be up-regulated or down-regulated in cancer, depending on the cancer entity (Kinugasa et al., 1998) (Dango et al., 2008) (Simeone et al., 2007). (Han et al., 2008) found abundant CEACAM5 and CEACAM6 in 9 gastric cancer cell lines, but no CEACAM1 was detected. In contrast, analysis of primary tumor samples from 222 patients showed cytoplasmic or cell membrane staining of CEACAM1 154845.doc •50·201200594 color. Membrane-bound forms are associated with enhanced angiogenesis (Zhou et al., 2009). (Kinugasa et al., 1998) also showed up-regulation in gastric adenocarcinoma. In some tumors, CEACAM1 is down-regulated in tumor cells, which leads to up-regulation of VEGF, and VEGF or hypoxic conditions induce CEACAM1 to be expressed in adjacent endothelium. . Thus, monoclonal antibodies against CEACAM1 block VEGF-induced endothelial tube formation (Oliveira-Ferrer et al., 2004; Tilki et al., 2006; Ergun et al., 2000). In particular, CEACAM5 has been tested as a target for anticancer drugs by, inter alia, vaccination methods. These studies have shown that CEACAM5 can be the standard for cellular immune responses (Cloosen et al., 2007; Marshall, 2003). A summary of the T cell epitopes of CEACAM5 is provided in (Sarobe et al., 2004). 0 Gas Channel 3 (CLCN3) CLCN3 is a C1 channel that can be volume-controlled and contributes to Regulatory Volume Reduction (RVD). This regulatory volume reduction is responsive to an increase in cell volume under conditions such as cell cycle or low permeation. However, this argument is still controversial (Wang et al., 2004) and the volume-reducing channel activated during apoptosis is different from CLCN3 (Okada et al., 2006). The performance of CLCN3 changes during the cell cycle, which peaks in the S phase (Wang et al., 2004). CLCN3 currents may be important in cancer-related processes in entities where CLCN3 is up-regulated, such as gliomas: tumor cells need to be treated with increased proliferative volume and encounter low-permeability conditions, such as in peritumoral edema (Ernest et al., 2005; Olsen et al., 2003; Sonth+eimer, 2008) ° 154845.doc -51 - 201200594 In addition, it has been reported that CLCN3 enhances etoposide resistance by increasing acidification of the late endocytic compartment (Weylandt et al. , 2007). siRNA-mediated blockade of CLCN3 expression can reduce the migration of nasopharyngeal carcinoma cells in vitro (Mao et al., 2008). DNAJC10 DNAJC10 is a member of the supramolecular ER-associated degradation (ERAD) complex that recognizes and unfolds proteins that are abnormally folded for efficient reverse translocation (Ushioda et al., 2008). This protein is shown to be elevated in hepatocellular carcinoma (Cunnea et al., 2007). Blocking DNAJC10 expression in ectodermal tumor cells with siRNA increased the cell death response to the chemotherapeutic drug fenretinide (Corazzari et al., 2007). ERdj5 has been shown to reduce neuroblastoma cell survival by down-regulating unfolded protein response (UPR) (Thomas and Spyrou, 2009). Eukaryotic translation initiation factor 2 subunit 3Y (EIF2S3) EIF2S3 is the largest subunit of the protein complex (EIF2) that recruits the starting methionine tRNA to the 40S ribosomal subunit (Clemens, 1997). The role of kinases that down-regulate EIF activity, such as RNA-dependent protein kinases (PKR), may be pro-apoptosis and tumor suppression (Mounir et al., 2009). In gastric cancer, it has been reported that the content of phosphorylated and unphosphorylated EIF2 is high, and redistribution to the nucleus is observed. This counter-regulation indicates that eIF2a is associated with gastrointestinal cancer (Lobo et al., 2000). Eukaryotic translation initiation factor 3 subunits L (EIF3L) EIF3L is one of 10 to 13 subunits of EIF3, which is associated with small ribosome subunits. EIF3 plays a role in preventing premature binding of large ribosomal subunits 154845.doc -52- 5 201200594. EIF3L is one of five subunits that have been reported to be not necessary for EIF3 formation (Masutani et al., 20〇7). Screening from antisense libraries indicated that down-regulation of EIF3L enhanced the anti-tumor activity of 5-fluorouracil in hepatocellular carcinoma cells (Doh, 2008). Epiplakin 1 (EPPK1) EPPK1 is the most plakin family gene of unknown function. The plaque gene has been shown to function in the cytoskeletal silk interconnection and anchoring it to the plasma membrane association adhesion junction (Yoshida et al., 2008). G protein coupled receptor 39 (GPR39)

GPR39 is a Gq protein-coupled receptor that is thought to be involved in gastrointestinal and metabolic functions (Yamamoto et al., 2009). Its signaling activates cAMP and serum response elements (Holst et al., 2004). The endogenous ligand of GPR39 may be zinc (Chen and Zhao, 2007). GPR39 is a novel cell death inhibitor that may represent therapeutic targets involved in processes including apoptosis and endoplasmic reticulum stress (eg, cancer) (Dittmer et al., 2008). GPR39 was found in human fetal kidney HFK and blastema-enriched stem-like wilms' tumor xenograft microarrays (Metsuyanim et al., 2009) and anti-multiple cell death stimuli The hippocampus cell line (Dittmer et al., 2008) was up-regulated. ERBB2/HER2/NEU ERBB2 is a member of the receptor tyrosine kinase EGFR family. The ligand is not known, but it is a preferred heterodimeric conjugate of other members of the HER family (Olayioye, 2001). In malignant tumors, HER2 can be used as an oncogene, mainly because the high amount of amplification of this gene can induce the protein in the cell membrane 154845.doc -53 - 201200594 quality overexpression and subsequently obtain favorable properties for malignant cells (Slamon et al. , 1 989). Excessive manifestations were observed in a certain percentage of many cancers, including gastric cancer. In most cases, it is associated with poor prognosis (Song et al., 2010) (Yonemura et al., 1991) (Uchino et al., 1993) (Mizutani et al., 1993). ERBB2 is a target of the monoclonal antibody trastuzumab (sold under the name Herceptin), which has been suggested to be combined with chemotherapy as a treatment option for patients with HER2-positive advanced gastric cancer (Meza-Junco et al., 2009; Van Cutsem et al., 2009). Another monoclonal antibody, pertuzumab, is in advanced clinical trials that inhibit the dimerization of HER2 and HER3 receptors (Kristjansdottir and Dizon, 2010). The selective overexpression of HER2 and HER3 in two tissue types of gastric cancer (intestinal and diffuse) is highly correlated with poor prognosis (Zhang et al., 2009). P-4 Integrin (ITGB4) Integrin mediates cell adhesion and signal transduction from the outside to the inside and from the inside to the outside. Integrin β-4 subunit and α-6 subunit heterodimerization. The resulting integrin promotes hemidesmosome formation between the cytokeratin cytoskeleton and the basement membrane (Giancotti, 2007). Integrin beta-4 has dual functions in cancer, on the one hand, it mediates stable adhesion, and on the other hand mediates pro-invasive signaling (including Ras/Erk and ΡΙ3Κ signaling) and angiogenesis (Giancotti, 2007; Raymond et al., 2007). It is overexpressed in many tumors as well as angiogenic endothelial cells, usually associated with progression and metastasis. Beta-4 integrin is highly expressed in gastric cancer, especially in stromal invasive cells (Giancotti, 2007; Tani et al., 1996). However, it is down-regulated in the undifferentiated type of gastric cancer with the deepening of tumor invasion by 154845.doc -54-201200594, which may be attributed to the gradual epithelial-mesenchymal transition because β-4 integrin is epithelial integrin (Yanchenko et al. Human, 2009) ° Lipocalin (LCN2) LCN2 or neutrophil gelatinase-associated lipocalin (NGAL) is a heterodimer with MMP9 linked in monomeric, homodimeric or disulfide-bonded A form of iron regulatory protein (Coles et al., 1999; Kjeldsen et al., 1993). Its performance is increased in several cancers and in some cases is related to progression. In mechanism, it stabilizes MMP9 and alters E-bone adhesion protein-mediated cell-cell adhesion, thereby increasing invasion. The complex of MMP-9 and LCN2 is associated with poor survival of gastric cancer (Kubben et al, 2007) (Hu et al, 2009). Although a clear tumor-promoting effect has been observed in various human tumors, some studies have shown that LCN2 inhibits the proliferative factors HIF-Ια, FA kinase phosphorylation, and VEGF synthesis, thus indicating that under alternative conditions, LCN2 is for example It also has anti-tumor and anti-metastasis effects in the formation of tumors of the colon, ovary and pancreas. (Bolignano et al., 2009; Tong et al., 2008). In ras-activated cancer, in addition to inhibiting tumor metastasis, LCN2 can also be used to inhibit tumor angiogenesis (Venkatesha et al., 2006). Succinic acid dehydrogenase complex subunit C (SDHC) SDHC is one of the four nuclear coded subunits of succinate dehydrogenase (mitochondrial complex II), which transfers electrons from succinic acid to ubiquinone. Thereby, a fumarate group and panthenol are produced. The lack of succinate dehydrogenase can cause GIST (McWhinney et al., 2007). Familial gastrointestinal stromal tumors may be caused by mutations in the 154845.doc -55-201200594 unit genes SDHB, SDHC, and SDHD, and abdominal paraganglioma associated with gastrointestinal tumors may be caused only by SDHC mutations (Pasini et al., 2008). ). In transgenic mice, mutated SDHC proteins produce oxidative stress and promote nuclear DNA damage, mutation induction, and eventual tumor formation (Ishii et al., 2005). Succinic acid dehydrogenase is considered a tumor suppressor (Baysal, 2003; Gottlieb and Tomlinson, 2005). A decrease in the amount of this enzyme complex can result in tumor formation (Eng et al., 2003). PDZ-binding kinase (PBK) PBK is a MEK3/6-associated MAPKK that activates p38 MAP kinase, for example, in the downstream of growth factor receptors (Abe et al., 2000; Ayllon and O'connor, 2007). JNK can be a secondary target (Oh et al., 2007). Since PBK is expressed in testis in adults (see below), it is presumed to function in spermatogenesis (Abe et al. '2000; Zhao et al., 2001). In addition, it promotes tumor cell proliferation and apoptosis resistance: it is phosphorylated and activated during mitosis, which is required for spindle formation and cytokinesis (Gaudet et al., 2000; Matsumoto et al. 2004; Park et al., 2009) (Abe et al., 2007). Other pro- and anti-apoptotic functions include down-regulation of p53 and histone phosphorylation (Park et al., 2006; Zykova et al., 2006) (Nandi et al., 2007). PBK has been classified as a cancer testis antigen (Abe et al, 2000; Park et al, 2006) and has been found to be overexpressed in many cancers. Polymerase (DNA-directed) δ3 Auxiliary Subunit (POLD3) DNA polymerase δ complex is involved in DNA replication and repair. It consists of proliferating cell nuclear antigen (PCNA), multiple unit replication factor C, and a 4-unit polymerase 154845.doc -56-201200594 complex (POLDl, POLD2, POLD3, and POLD4) (Liu and Warbrick, 2006). POLD3 plays a key role in the efficient recycling of PCNA during the ρ〇1 δ dissociation-binding cycle during extended DNA replication (Masuda et al., 2007). 0 Proteasome (precursor, megalin factor) 26S subunit non-ATP Enzyme 14 (PSMD14) PSMD14 is a component of the 26S proteasome. It belongs to the 19S complex (19S cap; PA700) and is responsible for deubiquitination during proteasomal degradation (Spataro et al., 1997). Excessive expression of PSMD14 in mammalian cells affects cell proliferation and responses to cytotoxic drugs such as vinblastine, cisplatin, and doxorubicin (Spataro et al., 2002). Inhibition of PSMD14 by siRNA in HeLa cells leads to decreased cell viability and increased polyubiquitinated protein content (Gallery et al., 2007). Down-regulation of PSMD14 by siRNA has a considerable effect on cell viability, leading to cell arrest in G0-G1 phase and eventual aging (Byrne et al., 2010). Proteasome (precursor, megalin factor) 26S subunit non-ATPase 2 (PSMC2) PSMC2 is part of the 26S proteasome system. It is a member of the three A family of ATPases with partner-like activity. This unit has been shown to interact with several basic transcription factors, so this unit is involved in transcriptional regulation in addition to its involvement in proteasome function. It has been shown that the 26S proteasome system in skeletal muscle can be activated by TNF-[alpha] (Tan et al., 2006) » HBx transgenic mice bearing the hepatitis B regulatory gene HBx in the germline and forming HCC, 154845.doc -57- 201200594 PSMC2 and other proteasome subunits are up-regulated in tumor tissues (Cui et al., 2006). The mRNA content of the ATPase subunit PSMC2 of the 19S complex is increased in cancer cachexia (Combaret et al., 1999). Protein tyrosine kinase 2 (PTK2) ΡΤΚ2 is a non-receptor tyrosine kinase that regulates integrin signaling and promotes tumor growth, progression, and metastasis (Giaginis et al., 2009); (Hauck et al., 2002). ) (Zhao and Guan, 2009)). PTK2 is suggested as a marker of carcinogenesis and cancer progression (Su et al, 2002; Theocharis et al, 2009; Jan et al, 2009). Excessive performance and/or increased activity occurs in a variety of human cancers, including gastric cancer. PTK2 also signals downstream of the gastrin receptor, which contributes to the proliferation of gastric cancer cells (Li et al. 2008b). 8% of gastric cancers showed Epstein-Barr virus (EBV). Subpopulations of human gastric cancer cell lines infected with EBV exhibit increased phosphorylation of PTK2 (Kassis et al., 2002). The degree of PTK2 tyrosine phosphorylation in gastric epithelial cells is reduced by cagA-positive H. pylori products. Four transmembrane protein 1 (TSPAN1) and four transmembrane protein 8 (TSPAN8) TSPAN1 and TSPAN8 belong to the four transmembrane protein family, which are characterized by four transmembrane domains and intracellular N-terminal and C-terminal, and It plays a role in many processes including cell adhesion, movement, activation, and tumor invasion. It typically forms macromolecular complexes with other proteins, such as integrins, on the cell surface (Tarrant et al., 2003; Serru et al., 2000). The function of TSP AN 1 is not known to be 'and may include a role in secretion (Scholz et al., 2009). TSPAN1 is over-expressed in several cancers, 154845.doc 58-201200594, and is usually associated with staging, progression, and worse clinical outcomes. Notably, there are reports that it is overexpressed in 56.98% of 86 cases of gastric cancer, and the excess performance is positively correlated with clinical stage, infiltration, and lymph node status, but negatively correlated with survival rate and tumor differentiation level (Chen et al., 2008). . There are also reports that TSPAN8 is a metastasis-associated gene in many types of tumors (PMID: 16467180). In gastrointestinal cancer, TSPAN8 performance is associated with poor prognosis (PMID: 16849554). Zinc finger protein 598 (ZNF598) ZNF598 is a protein of unknown function. Integrin-like metalloproteinase (ADAM10) ADAM10 plays a role in angiogenesis, development, and tumor formation. It is excessive in gastric cancer. A selective ADAM inhibitor against ADAM-10 is undergoing clinical trials for cancer treatment (PMID: 19408347). Matrix Metalloproteinase 12 (MMP12) MMP12 is a zinc endopeptidase that degrades elastin and many other matrix and non-matrix proteins and is involved in macrophage migration and angiogenesis inhibition (Chakraborti et al., 2003; Chandler et al. 1996; Sang, 1998). It also plays a role in the pathological processes of tissue destruction, such as asthma, emphysema and chronic obstructive pulmonary disease (COPD), rheumatoid arthritis and tumor growth (Cataldo et al., 2003; Wallace et al., 2008) » MMP12 Inhibitors are discussed as agents useful in the treatment of such conditions (churg et al, 2007; Norman, 2009). MMP12 is usually overexpressed in cancer and its function in cancer is not clear. Although it may be involved in matrix solubilization and is therefore involved in metastasis, it may also inhibit tumor growth via the production of angiostatin, which negatively affects angiogenesis, 154845.doc •59·201200594. It has been reported that the expression of MMP12 in GC is enhanced and shown to be beneficial: it is inversely associated with microvessel density, VEGF, grade of tumor differentiation, vascular invasion, lymph node metastasis, and recurrence. Patients with excessive MMP12 demonstrated significantly better survival (Cheng et al, 2010; Zhang et al. '2007b; Zhang et al, 2007a). Ribonucleotide reductase M2 (RRM2) RRM2 is one of two subunits of ribonucleoside reductase that produces deoxyribonucleotides from ribonucleotides. Excessive expression of RRM2 has been observed in tumors including gastric cancer, and this excess performance enhances the likelihood of metastasis (PMID: 18941749) (PMID: 19250552). Blockade of RRM2 by siRNA slows tumor growth in various species (mouse, rat, monkey) (PMID: 17929316; PMID: 17404105). Transmembrane protease serine 4 (TMPRSS4) TMPRSS4 is a type II transmembrane serine protease found on the cell surface that is highly expressed in several cancer tissues, including pancreatic cancer, colon cancer, and gastric cancer. The biological function of TMPRSS4 in cancer has not been known. TMPRSS4 has four splicing variants (Scott et al., 2001; Sawasaki et al., 2004). Performance in ovarian cancer is associated with staging (Sawasaki et al., 2004). TMPRSS4 is greatly elevated in lung cancer tissues, and siRNA expression of TMPRSS4 treated with small interfering RNA in lung cancer and colon cancer cell lines is associated with decreased cell invasion and cell matrix adhesion and regulation of cell proliferation (Jung et al., 2008). ). Deiodinated iodine thyroxine type II (DI02) 154845.doc •60- 201200594 DI02 converts the prohormone thyroxine (T4) into a biologically active 3,3',5-triiodothyronine (T3) ). It is highly expressed in the sacral gland and its performance and/or activity is found to be counter-regulated in squamous adenocarcinoma (de Souza Meyer et al., 2005) (Arnaldi et al., 2005). However, it has also been found in other tissues such as normal lung and lung cancer (Wawrzynska et al., 2003) and brain tumors (Murakami et al., 2000). Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) IGF2BP3 is mainly present in the nucleus, which binds to IGF2 mRNA in the nucleus and hinders its translation. It plays a role in embryogenesis and is downregulated in adult tissues. It is up-regulated in tumor cells and is therefore considered a carcinoembryonic protein (Liao et al., 2005). In many cancers including gastric cancer, excessive performance is found, which is associated with poor prognosis (Jeng et al., 2009) (Jiang et al., 2006). Peptides derived from IGF2BP3 were tested in cancer vaccination studies (Kono et al., 2009). Nuclear plaque protein B1 (LMNB1) Lamin layer B 1 is a nuclear layer matrix protein and is involved in nuclear stability, chromatin structure and gene expression. In the early stages of apoptosis, lamin degradation (Neamati et al., 1995) (Sato et al., 2008b; Sato et al., 2008a; Sato et al., 2009). LMNB 1 has a degree of performance in essentially all normal somatic cells, and preliminary studies indicate that it may be reduced during the onset of some cancers, including gastric cancer. In other cancers, such as hepatocellular carcinoma, LMNB 1 was found to be up-regulated and positively correlated with tumor stage 'size and number of knots (Lim et al., 2002).

Wingless MMTV integration site family member 5A 154845.doc •61 · 201200594 WNT5 A is a secretory signaling protein involved in developmental processes and tumor formation. Typical WNT5A signaling enables stem/progenitor cells to be maintained via Frizzled and LRP5/LRP6 receptors, whereas non-typical WNT5A signaling is controlled via coiling and ROR2/PTK/RYK receptors such as tissue polarity at the tumor-matrix interface, cells Adhere or move, thereby causing invasion (Katoh and Katoh, 2007). It may be a tumor suppressor in some cancers, but it is up-regulated in other cancers including gastric cancer, which promotes progression and metastasis in gastric cancer and leads to poor prognosis (Li et al., 2010) (Yamamoto et al., 2009) (Kurayoshi Et al., 2006). Fibroblast Activated Protein a (FAP) FAP is an integral membrane gelatinase. Its putative serine protease activity plays a role in controlling fibroblast growth or epithelial-mesenchymal interaction during development, tissue repair, and epithelial carcinogenesis (Scanlan et al., 1994). FAP has a potential role in cancer growth, metastasis, and angiogenesis via cell adhesion and metastasis processes and rapid degradation of ECM components. It is present in tumor cells that invade ECM, in reactive cancer-associated fibroblasts, and in endothelial cells involved in angiogenesis, but not in cells of the same type that are inactive. (Dolznig et al., 2005; Kennedy et al., 2009; Rettig et al., 1993; Rettig et al., 1994; Scanlan et al., 1994; Zhang et al., 2010). FAP expression has been found in gastric cancer cells and related matrix fibroblasts (Zhi et al, 2010) (Chen et al, 2006) (Mori et al, 2004; Okada et al, 2003). In a mouse model, FAP-expressing cells showed non-excessive tumor microenvironment immunosuppressive components (Kraman et al., 2010). In a mouse model of tumor vaccination, I54845.doc -62-8 201200594 FAP was successfully used as a target for CD8+ and CD4+ T cell responses (Loeffler et al., 2006; Wen et al., 2010) (Lee et al. , 2005) (Fassnacht et al., 2005). Exosome protein complex subunit Y (COPG); exosome protein complex subunit Y2 (COPG2); exosome protein complex subunit pi (COPBl) C0PG, COPG2 and COPB1 are non-caurnin envelope The capsule binds to the subunit of the foreign body complex (also known as coat protein complex 1; C0PI). The C0PI is mediated by the capsular sac from the retrograde transport of the ER from the Golgi and transport in the Golgi (Watson et al., 2004). It may also be involved in antegrade transport (Nickel et al., 1998). Retrograde transport specifically regulates EGF-dependent nuclear transport of EGFR, which binds to COPG (Wang et al., 2010). COPG was found to be overexpressed in lung cancer cells and lung cancer-associated microvascular endothelial cells (Park et al., 2008). The generally expressed sequence of COPG2 is 80% identical to GOPG (Blagitko et al., 1999). COPG2 may replace a functionally undesirable GOPG to form a COPI-like complex (Futatsumori et al., 2000). Blocking of COPD1 expression in a cell line of cystic fibrosis transmembrane conductance regulator (CFTR) suggests that the exosome complex is involved in the transport of CRTR to the plasma membrane (Denning et al., 1992) (Bannykh et al., 2000). ). Ubiquitin-binding enzyme E2S (UBE2S) UBE2S is a cofactor for the late-stage complex (APC). The late-promoting complex is an E3 ubiquitin ligase that regulates the end of mitosis by targeting cell cycle regulators and Gl » UBE2S The ubiquitin chain was extended after the receptor was ubiquitinated by other components 154845.doc -63-201200594 (Wu et al., 2010). UBE2S also targets VHL proteins to degrade proteasomes, thereby stabilizing HIF-lct (Lim et al., 2008) and may support proliferation, epithelial-mesenchymal transition and metastasis (Chen et al., 2009) (Jung et al., 2006). . UBE2S is overexpressed in several cancer entities. Kinesin family member ll (KIFll) KIF 11 is required for assembly of a bipolar mitotic spindle. It has been found to be up-regulated in several cancers and is often associated with clinical pathology parameters (Liu et al., 2010) (Peyre et al., 2010). Small molecule inhibitors of KIF11, such as S-triphenylmethyl-L-cysteine (STLC), which is a potential anticancer drug, blocks cells in mitosis and promotes cancer cell apoptosis (Tsui et al., 2009) (Wiltshire et al., 2010) (Ding et al., 2010). Clinically, KIF 11 inhibitors only show less activity (Kaan et al., 20 1 0; Tunquist et al., 2010; Wiltshire et al., 2010; Zhang and Xu, 2008). Integrin-like metalloproteinase domain 8 (ADAM8)

ADAM8 was originally thought to be immune-specific ADAM, but it was later found to be present in other cell types, usually in conditions involving inflammation and ECM remodeling, including cancer and respiratory diseases such as asthma (Koller et al., 2009). . Many ADAM substances, including ADAM8, are expressed in human malignancies, in which they are involved in regulating growth factor activity and integrin function, thereby promoting cell growth and invasion, but the exact mechanism of these phenomena is still unclear. (Mochizuki and Okada 2007). In mouse gastric tumors, ADAM8 and other ADAMs are increased, possibly due to enhanced signaling by EGFR 154845.doc -64-8 201200594 (Oshima et al., 2011). Cell division cycle 6 homolog (Saccharomyces cerevisiae) (CDC6) CDC6 is required for initiation of DNA replication. It is located in the nucleus during G1 but shifts to the cytoplasm at the beginning of the S phase. CDC6 also regulates replication checkpoint activation via interaction with ATR (Yoshida et al., 2010). CDC6 counter-regulation can result in the inactivation of the three major tumor suppressor genes (pl6INK4a and p1 5INK4b, both of which are retinoblastoma pathway activators; and ARF, which is a p53 activator) (Gonzalez) Et al., 2006). Blockade of siRNA expression of CDC6 prevents proliferation and promotes apoptosis (Lau et al., 2006). CDC6 is upregulated in cancers including gastric cancer (Nakamura et al., 2007) (Tsukamoto et al., 2008) 〇F2R coagulation factor 11 (thrombin) receptor (F2R) F2R is also known as protease activated receptor (PAR1). A G protein coupled receptor. Signaling of PARI, PAR2, and PAR4 regulates calcium release or activation of mitogen-activated protein kinases and causes platelet aggregation, vasodilation, cell proliferation, cytokine release, and inflammation (Oikonomopoulou et al., 2010). F2R is thought to be involved in endothelial cell proliferation and tumor cell proliferation and angiogenesis, and is overexpressed in many types of invasive and metastatic tumors. Its performance is directly related to the degree of cancer invasion (Garcia_Lopez et al., 2010) (Lurje et al., 2010). In gastric cancer cells, F2R activation triggers a series of responses that promote tumor cell growth and invasion, such as NF-κΒ, EGFR, and tendin protein C (TN-C) overexpression (Fujimoto et al., 2010). Therefore, F2R expression in gastric cancer was found to be associated with wall invasion 154845.doc 65·201200594 degrees, peritoneal dissemination, and poor prognosis (Fujimoto et al., 2008). Mouse monoclonal anti-human PAR1 antibody (ATAP-2) and PAR1 agonist peptide TFLLRNPNDK, which recognize the epitope in the N-terminus of the thrombin receptor, have been described (Hollenberg and Compton 2002; Mari et al., 1996; Et al., 1995). The olfactory protein 4 (OLFM4) function is largely unknown in OLFM4 in inflamed colonic epithelial cells and in many human tumor types, especially in digestive system tumors (Koshida et al., 2007). OLFM4 is a robust marker of stem cells in the human gut and is labeled as a subset of colorectal cancer cells (van der Flier et al., 2009). OLFM4 inhibits the pro-apoptotic protein GRIM-19 (Zhang et al., 2004) (Huang et al., 2010), modulating the cell cycle and promoting S phase transition in cancer cell proliferation. In addition, OLFM4 is associated with cancer adhesion and metastasis (Yu et al., 2011b). Enhanced overexpression of OLFM4 in murine prostate tumor cells results in faster tumor formation in homologous hosts (Zhang et al, 2004). OLFM4 was found to be overexpressed in the GC (Aung et al., 2006). Inhibition of OLFM4 expression induces apoptosis in gastric cancer cells in the presence of cytotoxic agents (Kim et al., 20 10). In addition, serum OLFM4 concentrations in patients with pre-operative GC increased compared to healthy donors (Oue et al., 2009). OLFM4 was identified as a novel target gene for retinoic acid (RA) and a depurinating base 5-aza-2'-deoxynucleotide. These two agents have been shown to be effective in treating certain patients with osteomyelitis (Liu et al., 201 0).

Thy-Ι cell surface antigen (THY1)

Thy-1 (CD90) is a GPI-anchored glycoprotein found on many cell types including T cells, neuronal 'endothelial cells, and fibroblasts I54845.doc 66·201200594. Thy-1 involves processes including adhesion, nerve regeneration, tumor growth, tumor suppression, migration, cell death, and T cell activation. (Rege and Hagood 2006b; Rege and Hagood 2006a) (Jurisic et al., 2010). Thy-1 appears to be a marker of adult angiogenesis, but is not a marker of embryonic angiogenesis (Lee et al., 1998). In addition, it is considered as various stem cells (mesenchymal stem cells, liver stem cells ("oval cells") (Masson et al., 2006), keratinocyte stem cells (Nakamura et al., 2006), and hematopoietic stem cells (Yamazaki et al., 2009). ) the marker. Thy-Ι is up-regulated in several cancers, including gastric cancer and GIST, and it is therefore suggested that Thy-Ι can be used as a marker for such cancers (Yang and Chung 2008; Zhang et al., 2010) (0ikonomou et al., 2007). Center protein 250 kDa (CEP250)

Cep250 plays a role in the cohesion of microtubule tissue centers (Mayor et al., 2000). It is also known as the centrosome Nek2-related protein or C-Napl because it colocalizes with the serine/threonine kinase Nek2 and is a substrate for the serine/threonine kinase Nek2. The junction between Nek2 kinase and its receptor regulatory center (Bahmanyar et al., 2008). At the onset of mitosis, when the centrosome separates to form a bipolar spindle, C-Napl is phosphorylated and subsequently dissociated from the centrosome. In vitro experiments have shown that excessive performance of Cep250 can damage microtubule tissue at the center of the body (Mayor et al., 2002). Hypoxia-inducible factor Ια subunit (basic helix-loop-helix transcription factor) (HIF1A) HIF1A is an oxygen-sensitive subunit of hypoxia-inducible factor (HIF), the hypoxia 154845.doc •67-201200594 induction factor is A transcription factor that is active under hypoxic conditions often found in tumors. It mediates the transcription of more than 60 genes associated with survival, glucose metabolism, invasion, metastasis, and angiogenesis, such as VEGF. HIF1 is overexpressed in many cancers', which are often associated with poor prognosis and are considered to be the focus of pharmacological treatment (Griffiths et al., 2005).

Quintero et al., 2004; Stoeltzing et al., 2004) (Zhong et al., 1999). In gastric cancer, HIF1A promotes angiogenesis (Nam et al., 2011) and is associated with tumor size, lower differentiation, tumor stage, shorter survival (Qiu et al., 2011) and metastasis (Wang et al., 2010) (Han Et al., 2006; Kim et al. '2009; Oh et al., 2008; Ru et al., 2007). It is also thought to cause resistance to chemotherapeutic drugs (such as 5-FU) and reduce intracellular drug accumulation via inhibition of drug-induced apoptosis (Nakamura et al., 2009) (Liu et al., 2008). The HIF-lot-inhibitor 2-methoxy-estradiol significantly reduces the metastasis of gastric cancer cells (Rohwer et al., 2009). v-Ki-ras2 Kristin rat sarcoma virus oncogene homolog (KRAS) KRAS is a member of the small GTPase superfamily and is involved in many signal transduction pathways (such as MAPK and AKT-mediated pathways) that may be carcinogenic ) The early steps of the original oncogene. Substitution of a single amino acid activates the mutation, thereby producing a transforming protein that plays a key role in various malignancies including gastric cancer (Capel la et al., 1991). Carcinogenic mutations in KRAS are not common in gastric cancer. In the gastric cancer subset, the KRAS locus is amplified, resulting in excessive expression of KRAs. Therefore, gene amplification may be the molecular basis for KRAS overactivation in gastric cancer (Mita et al., 2009). The mutated KRAS dual gene can be 154845.doc-68-201200594 to promote hypoxia-driven VEGF induction (Kikuchi et al, 2009; Zeng et al, 2010). Mutant KRAS can also be detected in serum or plasma of cancer patients and is therefore recommended as a readily available tumor marker (Sorenson, 2000). The peptide KRAS-001 was derived only from one of the two splicing variants - NP_004976 (188 amino acids) and not from the splicing variant NP_203524 (189 amino acids). The difference between these splicing variants lies in their last exon, which is the location of KRAS 001. Non-SMC agglutinin I complex subunit G (NCAPG) NCAPG is a part of the agglomerated protein I complex, which is composed of chromosome structure maintenance (SMC) protein and non-SMC protein, and regulates chromosome condensation and separation during mitosis. (Seipold et al., 2009). Overexpression of NCAPG has been found in many tumors, including nasopharyngeal carcinoma (Li et al, 2010), hepatocellular carcinoma (Satow et al, 2010), and melanoma (Ryu et al, 2007). In normal tissues, NCAPG shows the highest performance in the testes. It has been suggested as a possible proliferative marker and potential prognostic indicator in cancer (Jager et al., 2000). Topoisomerase (DNA) IIa (TOP2A) and topoisomerase (DNA) Iip (TOP2B) TOP2A & TOP2B encodes a highly homologous isoform of DNA topoisomerase, DNA topoisomerase in the transcription process Control and change the topological state of DNA, and participate in chromosome coagulation, stain separation, replication and transcription. Topoisomerases are targets for several anticancer drugs such as anthracyclin, and multiple mutations are associated with drug resistance (Kellner et al., 2002) (Jarvinen and Liu, 2006) ° TOP2A (not TOP2B) Cell 154845.doc -69- 201200594 Required for proliferation. It is located adjacent to the HER2 oncogene and is amplified in most HER2 amplified breast tumors and breast tumors without HER2 amplification (Jarvinen and Liu, 2003) and many other tumor entities. In the gastric cancer subset, TOP2A amplification and overexpression are also found, which usually occurs with HER2 (Varis et al., 2002) (Liang et al., 2008). Laminin Y2 (LAMC2) laminin is the major non-collagen component of the basement membrane. It is involved in cell adhesion, differentiation, migration, signaling, and metastasis. The γ2 chain together with the α3 and β3 chains constitutes laminin 5. LAMC2 promotes invasive growth of human cancer cells in vivo. It is highly expressed before human cancer invasion and its performance is associated with poor prognosis (Tsubota et al., 2010). The laminin 5 lysate produced by ΜΜΡ-2 is capable of activating EGFR signaling and promoting cell movement (Schenk et al., 2003). In gastric cancer, LAMC2 can be induced by EGFR family members or Wnt5a, and its invasive activity depends on LAMC2 (Tsubota et al., 2010) (Yamamoto et al., 2009). Aryl hydrocarbon acceptor (AHR) AHR binds to planar aromatic hydrocarbons such as T.CDD (2,3,7,8-tetrasodibenzo-p-dioxine) and mediates exogenous biological metabolism Gene transcription of enzymes (such as cytochrome P450 enzymes) also plays a role in cell cycle progression (Barhoover et al., 2010). AhR is thought to be partially involved in the pro-tumor activity of dioxetine because it has pro-proliferative and anti-apoptotic functions and can lead to cell-cell contact counter-regulation, dedifferentiation and motor enhancement (Watabe et al., 2010). (Dietrich and Kaina 2010) (Marlowe et al., 2008). AHR performance can be down-regulated by TGF-β (Dohr and Abel 1997; I54845.doc ·70· _ 201200594

Wolff et al., 2001), and induced by Wnt or β-catenin signaling (Chesire et al., 2004). AHR overexpression is found in many cancers including gastric cancer, in which AHR is associated with frequent CYP1A1 performance (Ma et al, 2006). The expression and nuclear translocation of AHR in gastric cancer is higher than in normal tissues, and its expression gradually increases during carcinogenesis (Peng et al., 2009a). AhR pathway activation may enhance gastric cancer cell invasiveness by c-Jun-dependent induction of MMP-9 (Peng et al, 2009b). In a mouse model, the expression of a constitutively active mutant of aryl hydrocarbon receptor (CA-AhR) leads to gastric tumorigenesis, which is associated with increased mortality (Andersson et al., 2002; Kuznetsov et al., 2005). The function of AhR in cancer appears to be unclear, as some studies have also indicated that it has tumor suppressor activity (Gluschnaider et al., 2010) (Fan et al., 2010). Hyaluronic Acid Mediated Exercise Receptor (RHAMM) (HMMR) HMMR can be present on the cell surface, which binds to hyaluronic acid (HA) on the cell surface and interacts with the HA receptor CD44. This interaction plays a role in processes such as cell movement, traumatic soreness and invasion (Gares and Pilarski, 2000). Within the cell, HMMR is associated with the cytoskeleton, microtubules, central body, and mitotic spindle and plays a role in controlling the integrity of the mitotic spindle. HMMR is overexpressed in several cancer tissues (Sohr and Engeland, 2008). HA is presumed to protect cancer cells from immune attacks. Serum HA is usually increased in metastatic patients (Delpech et al., 1997). HMMR has been identified as a promising tumor-associated antigen and a prognostic factor in AML and CLL. Peptides derived from HMMR have been used in anti-leukemia vaccines. In vitro immunogenicity of HMMR-001 was also tested but not for vaccination with 154845.doc 71 201200594 (Tzankov et al., 2011) (Greiner et al., 2010; Schmitt et al., 2008; Tabarkiewicz and Giannopoulos, 2010). (Greiner et al., 2005). HMMR overexpression is also found in several other cancers, which are often associated with poor prognosis. HMMR is also overexpressed in gastric cancer, which is usually associated with CD44 and is presumed to promote invasion and metastasis (Li et al. 1999) (Li et al., 2000a) (Li et al., 2000b). TPX2 microtubule-associated homolog (with Xenopus laevis) (τρχ2) TPRX2 is a proliferation-associated protein expressed in the s, G(2), and sputum phases of the cell cycle and considered to be a proliferative target (Cordes et al. 2010). Normal microtubule nucleation requires TPRX2, for example for assembly of a mitotic spindle. TPX2 recruits and activates Aurora kinase A (Bird and Hyman, 2008; Moss et al. 2009). The acidification of τρχ2 with Polo-like kinase 1 increases its ability to activate Aurora kinase A (Eckerdt et al., 2009). TPX2 is overexpressed in many tumor types and is often co-expressed with Aurora kinase _A (Asteriti et al., 2010). Examples of overexpression of TPX2 that have been found (often associated with poor prognosis or later) are meningioma (Stuart et al., 2010), lung cancer (Kadara et al., 2009) (Lin et al., 2006; Ma et al., 2006) (Manda Et al '1999) and hepatocellular carcinoma (shigeishi et al, 2009b) (Satow et al, 2010) (Wang et al, 2003). Thus the invention relates to a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 95 or having at least 80% homology to SEQ ID NO: 1 to SEQ ID NO: 95 A variant, or a variant thereof that induces a cross-reaction of a tau cell with the peptide, wherein the peptide is not a full length polypeptide. The invention further relates to a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1 to 154845. doc - 72-8 201200594 SEQ ID NO: 95, or having SEQ ID NO: 1 to SEQ ID NO: 95 A variant of at least 80% homology, wherein the peptide or variant has a total length of from 8 to 100, preferably from 8 to 30, and most preferably from 8 to 14 amino acids. The invention further relates to the previously described peptides which are capable of binding to a class I or a class II human major histocompatibility complex (MHC) molecule. The invention further relates to the previously described peptide, wherein the peptide consists or consists essentially of the amino acid sequence of SEQ ID No. 1 to SEQ ID No. 95. The invention further relates to a peptide as described above, wherein the peptide is modified and/or comprises a non-peptide bond. The invention further relates to a peptide as described above, wherein the peptide is a fusion protein, in particular an N-terminal amino acid comprising an HLA-DR antigen-associated invariant chain (Π). The invention further relates to a nucleic acid encoding a peptide as described above, provided that the peptide is not a complete human protein. The invention further relates to a nucleic acid as previously described which is DNA, cDNA, PNA, CAN, RNA, and possibly a combination thereof. The invention further relates to an expression vector capable of expressing a nucleic acid as previously described. The invention further relates to a previously described peptide, a previously described nucleic acid or a previously described expression vector for use in a medicament. The invention further relates to a host cell comprising the aforementioned nucleic acid or the aforementioned expression vector. The invention further relates to said host fine 154845.doc-73-201200594 cells which are antigen presenting cells. The invention further relates to said host cell, wherein the antigen presenting cell is a dendritic cell. The invention further relates to a method of formulating a peptide comprising culturing the host cell and isolating the peptide from the host cell or a culture medium thereof. The invention further relates to a method for the preparation of activated cytotoxic tau lymphocytes (CTL) in vitro. The method comprises in vitro linking a CTL to a human I or a class II MHC molecule carrying an antigen. These molecules are in a suitable antigen presenting cell. The surface is expressed for a sufficient period of time to initiate CTL in an antigen-specific manner, wherein the antigen is any one of the peptides. The invention further relates to the method wherein the antigen is loaded into an I or steroid MHC molecule expressed on the surface of a suitable antigen presenting cell by binding to a sufficient amount of antigen containing the antigen-presenting cell. The invention further relates to the method, wherein the antigen presenting cell comprises an expression vector which is capable of expressing a peptide comprising hydrazine ID NO 1 to SEQ ID NO 33 or the variant amino acid sequence. The invention further relates to a cytotoxic T lymphocyte (CTL) prepared by the method, which selectively recognizes a cell which aberrantly expresses a polypeptide comprising one of said amino acid sequences. The invention further relates to a method of killing a target cell of a patient, wherein the target cell of the patient aberrantly expresses a polypeptide comprising any of the amino acid sequences, the method comprising administering to the patient an effective amount of the above-described toxic T lymphocytes (CTL). The invention further relates to any of said peptides, said one nucleic acid, said 154845.doc - 74 - 8 201200594 expression vectors, said one cell, said one acting as a medicament or a pharmaceutical agent for initiating cytotoxic tau lymphocytes use. The invention further relates to a method of use wherein the medicament is a vaccine. The invention further relates to a method of use wherein the agent has anticancer activity. The invention further relates to the use, wherein the cancer cell is a gastric cancer cell, a gastrointestinal cancer cell, a colorectal cancer cell, a pancreatic cancer cell, a lung cancer cell or a renal cancer cell. The invention further relates to a particular marker protein useful as a prognosis for gastric cancer. Furthermore, the invention relates to these new targets for the treatment of cancer. As provided herein, the literature has described ABL1, ADAM10, AHR, CCND2, CDC6, CDK1, CEACAM1, CEACAM5, CEACAM6, CEACAM6, COL6A3, compared to normal stomach and other living tissues (eg liver, kidney, heart). EIF2S3, LOC255308, EPHA2, ERBB2, ERBB3, F2R, FAP, HMMR, HSP90B1, IGF2BP3, ITGB4, KIF2C, KRAS, LAMC2, LCN2, MET, MMP11, MMP12, MMP3, MST1R, NUF2, OLFM4, PROM1, RRM2, THY1 Proteins encoded by TMPRSS4, TOP2A, TSPAN1, WNT5A, HIF1A and PTK2 are overexpressed in gastric cancer. From ABL1, ADAM10, ADAM8, AHR, ASPM, ATAD2, CCDC88A, CCNB1, CCND2, CCNE2, CDC6, CDK1, CEACAM1, CEACAM5, CEACAM6, CEACAM6, I54845.doc -75· 201200594 CLCN3, COL6A3, EPHA2, ERBB2, ERBB3, F2R, FAP, HIF1A, HMMR, HSP90B1, IGF2BP3, IQGAP3, ITGB4, KIF11, KIF2C, KRAS, LAMC2, LCN2, MET, MMP11, MMP3, MST1R, MUC6, NCAPG, NFYB, NUF2, OLFM4, PBK, PLK4, PPAP2C, Proteins encoded by PROM1, PTK2, RRM2, SIAH2, THY1, TOP2A, TPX2, TSPAN1, TSPAN8, UBE2S, UCHL5, and WNT5A have been shown to play an important role in tumor formation because they are involved in malignant transformation, cell growth, proliferation, and angiogenesis. Or invade normal tissues. Similarly, for proteins encoded by DNAJC10, EIF2S3, EIF3L, POLD3, PSMC2, PSMD14, and TMPRSS4, there is also evidence for cancer-related functions. Proteins encoded by PROM1, WNT5A, SMC4, PPAP2C, GPR38, OLFM4, and THY1 are shown to be highly expressed and/or play an important role in stem cells and/or cancer stem cells. PROM1 is considered to be a marker for gastric cancer stem cells, but the data is still controversial. Cancer stem cells are a subset of tumor cells that have the self-renewal potential needed to maintain tumor growth. These cells reside in a special and highly organized structure, the so-called cancer stem cell sputum required to maintain the self-renewal potential of cancer stem cells. Proteins AHR, ASPM, ATAD2, CCNB1, CCND2, CCNE2, CDK1 (CDC2), CEACAM1, CEACAM5, CEACAM6, CEACAM6, COL6A3, EPHA2, ERBB2, ERBB3, F2R, FAP, HIF1A, HMMR, HSP90B1, IGF2BP3, ITGB4, KIF11, KIF2C, KRAS, LAMC2, • 76-154845.doc 201200594 LCN2, LMNB1, MET, MMP11, MMP3, MST1R, MUC6, NCAPG, NUF2, OLFM4, PBK, PPAP2C, PROM1, PTK2, TMPRSS4, TPX2, TSPAN1 and WNT5A in tumor Excessive performance in the show is associated with advanced disease stages and poor prognosis in patients. Accordingly, the present invention proposes a method of identifying an animal, preferably a human who may have gastric cancer. In one embodiment, the likelihood is determined to be 80% to 100%. One such method comprises determining the level of at least one of the proteins MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 from a tumor sample of a subject animal. In one embodiment, the sample is obtained by radical surgery. In another embodiment, the sample is obtained by needle biopsy. When the level of measurement by MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 is increased by 20% or more relative to the level of measurement in benign epithelial cells of the same specimen, the test animal is determined to have gastric cancer. The more different proteins of the group consisting of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 are up-regulated, and the test animals have a higher probability of being confirmed as having gastric cancer. In one embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, or MUC6 levels are determined in situ. In another embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, or MUC6 levels In vitro assay. In another embodiment, the MST1R, UCHL5, SMC4, NFYB, I54845.doc-77-201200594 PPAP2C, AVL9, UQCRB or MUC6 levels are determined in vivo. In a preferred embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 levels are determined by laser capture microscopy combined with immunoblotting. In a preferred embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 levels are determined using specific antibodies to MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6. In a preferred embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 levels are determined by a primer-containing PCR method in which the primers encode MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6. Specific primers for mRNA. In another preferred embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 levels are determined by primer-containing nucleotide probes, wherein the probes encode MST1R, UCHL5, SMC4, NFYB, PPAP2C, Specific probe for mRNA for AVL9, UQCRB or MUC6. In one such embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 levels are determined using Northern blotting. In another embodiment, the MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 levels are determined using a ribonuclease protection assay. In other embodiments, immunological tests such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and Western blotting may be used to detect body fluid samples (eg, blood, serum, sputum, urine, or peritoneal fluid). MST1R, 154845.doc -78· 8 201200594 UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 polypeptides. Samples, tissue samples, and cell samples (eg, ovary, lymph nodes, ovarian surface epithelial cell debris, lung samples, liver samples, and any liquid samples containing cells (eg, peritoneal fluid, sputum, and pleural effusion) Testing by decomposing and/or dissolving tissue or cell samples and detecting the polypeptide using immunoassays (eg, ELIS A, RIA, or Western blotting). Such cells or tissue samples can also be analyzed using nucleic acid-based methods, eg, Transcriptional polymerase chain reaction (RT-PCR) amplification, Northern hybridization, or trough or dot blotting. In order to see the distribution of tumor cells in tissue samples, diagnostic tests that preserve the tissue structure of the sample may be used separately (eg, immunization) Histochemical staining, RNA in situ hybridization, or in situ RT-PCR techniques are used to detect gastric cancer marker polypeptides or mRNA. For in vivo localization of tumors, imaging studies, such as magnetic resonance imaging (MRI), may be used Introduce a specific binding to MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 polypeptides (especially peptides restricted to the cell surface) An antibody, wherein the antibody is covalently bound or otherwise coupled to a paramagnetic tracer (or other suitable detectable motif, depending on the imaging technique used); in addition, unlabeled tumor marker specificity The position of the antibody can be detected using a secondary antibody coupled to a detectable motif. Furthermore, the present invention further provides for the composition of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 polymorphism, and fragments thereof (including functions) Chimeric/fusion proteins/peptides of sexual, proteolytic and antigenic fragments. Fusion partners or fragments of hybrid molecules provide suitable stimulating CD4+ T cells. 154845.doc -79-201200594 when epitope. CD4+ stimulating epitope It is well known in the art and includes epitopes identified in tetanus toxoid. In a further preferred embodiment, the peptide is a fusion protein, in particular comprising an N-terminal amino acid of the HLA-DR antigen-associated invariant chain (Ii) In one embodiment, the peptide of the invention is a truncated version of a protein fragment and another polypeptide portion (if the human polypeptide portion contains a plurality of inventive amino acid sequences) Protein or fusion protein. The invention also includes an antibody to MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 polypeptide, chimeric/fusion of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 polypeptides. Antibodies to proteins, as well as antibodies to MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 polypeptide fragments (including proteolytic and antigenic fragments) and antibodies to the chimeric/fusion proteins/peptides of these fragments. Furthermore, the use of these antibodies against cancer, particularly against the prognosis of gastric cancer, is also part of the present invention. The antibody of the present invention may be a polyclonal antibody, a monoclonal antibody, and/or a chimeric antibody. An immortalized cell line that produces a monoclonal antibody of the invention is also part of the invention. One of ordinary skill in the art will appreciate that, in some instances, higher expression of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, or MUC6 as a tumor marker gene suggests that subjects with gastric cancer have a poor prognosis. For example, higher levels of expression of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, or MUC6 may indicate a relatively large tumor volume and a higher tumor burden (eg, more 154845.doc -80 - 201200594 metastasis), or The degree of malignancy of the tumor is relatively high. The higher the overexpression of different proteins consisting of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6, the worse the prognosis. The diagnostic and prognostic methods of the invention involve the use of known methods, for example: antibody-based methods to detect MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 polypeptides, as well as nucleic acid hybridization and/or amplification-based Methods for detecting mRNAs of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 In addition, since rapid destruction of tumor cells often leads to autoantibody production, the gastric cancer tumor markers of the present invention can be used for serological detection (for example, An ELISA test of the tester's serum) to detect autoantibodies against MST1R, UCHL5, SMC4 'NFYB, PPAP2C, AVL9, UQCRB or MUC6 in the subject. The levels of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 polypeptide-specific antibodies are at least about 3 times higher (preferably at least 5 or 7 times, most preferably at least 10 or 20 times), compared to the control sample, This level suggests gastric cancer. Local, intracellular, and secreted MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, and MUC6 polypeptides may be used for biopsy analysis, eg, tissue or cell samples (including, for example, liquid samples obtained from peritoneal fluid) To determine a tissue or cell sample containing gastric cancer cells. The specimen can be analyzed as a complete tissue or whole cell sample, and the tissue or cell sample may also be classified and/or dissolved according to the type of diagnostic test required. For example, a sample or sample may be analyzed for whole tissue or whole cells of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, and MUC6 polypeptides or mRNA levels by in situ, immunohistochemistry, in situ hybridization of mRNA. Method or in situ RT-PCR. The skilled person knows how to handle tissue or cell analysis for peptide or mRNA levels, using immunological methods (such as ELISA, immunoblotting or equivalent methods), or using nucleic acid-based assays (such as RT-PCR, Northern hybridization or troughing). Or dot blotting) analysis of mRNA levels. Kit for measuring expression levels of MST1R, UCHL5 'SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6. The present invention proposes a kit for detecting an increase in the expression levels of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 as a gastric cancer marker gene in a subject. A kit for detecting a gastric cancer marker polypeptide preferably comprises an antibody that specifically binds to a selected gastric cancer marker polypeptide. A kit for detecting gastric cancer marker mRNA preferably comprises one or more nucleic acids that specifically hybridize to MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 mRNA (eg, one or more oligonucleotide primers or probes) Needles, DNA probes, RNA probes, or probe templates for RNA production). In particular, antibody-based kits can be used to detect the presentation, and/or measurement of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 that specifically bind to antibodies or immunoreactive fragments thereof. The kit can include an antibody that reacts with an antigen and a reaction that detects an antigen-containing antibody. The kit can be an ELISA kit and can contain a control 154845.doc -82 - 8 201200594 (eg, a specified amount of a particular gastric cancer marker polypeptide), a primary antibody and a secondary antibody (where appropriate), any other necessary as described above. Reagents such as: detectable elements, enzyme substrates, and colored reagents. Additionally, the diagnostic kit can be a kit that generally consists of the components and reagents described herein. A nucleic acid-based kit can be used to detect and/or measure MST1R by detecting and/or measuring mRNAs of BMST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, and MUC6 in a sample (eg, tissue or cell). Expression levels of UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6. For example, an RT-PCR kit for detecting increased expression of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, and MUC6 preferably comprises sufficient oligonucleotide primers to reverse transcribe gastric cancer mRNA into cDNA and cDNA for gastric cancer markers PCR amplification is also performed, preferably also containing control PCR template molecules and primers to quantify appropriate negative and positive controls as well as internal controls. One of ordinary skill in the art will understand how to select suitable primers for reverse transcription and PCR reactions, as well as suitable control reactions. This guidance can be found, for example, in "Current Protocols in Molecular Biology" by F. Ausubel et al., New York, N.Y., 1997. Many mutants of RT-PCR are well known in the art. The immunotoxin can be targeted to MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 as therapeutic targets for gastric cancer prevention and treatment. For example, an antibody molecule that specifically binds to cell surface-restricted MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB, and MUC6 polypeptides can be covalently bound to a radioisotope or other toxic compound. Administration of the antibody 154845.doc 83·201200594 The antibody conjugate is such that binding of the antibody to its cognate gastric cancer polypeptide results in the dry delivery of the therapeutic compound to the gastric cancer cell, thereby treating ovarian cancer. The therapeutic component can be a toxin, a radioisotope, a drug, a chemical or a protein (see, for example, Bera et al. "Pharmacokinetics and antitumor activity of a bivalent disulfide-stabilized Fv immunotoxin with improved antigen binding to erbB2"

Cancer Res. 59:4018-4022 (1999)) · For example, the antibody may be linked or covalently bound to a bacterial toxin (eg, diphtheria toxin, Pseudomonas aeruginosa exotoxin A, cholera toxin) or a plant toxin (eg 蓖Toxin) to target the delivery of toxins to cells expressing MST1R, UCHL5 'SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6. This immunotoxin can be delivered to the cell, and once bound to a cell surface localized gastric cancer marker polypeptide, a toxin conjugated to a gastric cancer marker-specific antibody will be delivered to the cell. Furthermore, for any MST1R, UCiiL5, SMC4, NFYB, PPamc, AVL9, UQCRB* Muc6 polypeptide containing a specific ligand (eg, a ligand that binds to a cell surface-deficient f-protein), the ligand can be substituted for the antibody to Toxic compounds act on gastric cancer cells as described above. The term "antibody" in this context is defined broadly and includes both polyclonal and polyclonal. Includes monoclonal antibodies. In addition to intact immunoglobulin molecules, the term "antibody" also includes fragments or polymers of these immunoglobulin molecules and humanized immunoglobulin molecules, as long as they exhibit any of the desired properties described herein (eg, 'gastric cancer Specific binding of the polypeptides, transfer of the toxin to gastric cancer cells and/or gastric 154845.doc-84-201200594 cancer marker, activity of the polypeptide when the expression level of the gastric cancer marker gene is increased. Whenever possible, the antibodies of the invention can be purchased from commercial sources. The antibodies of the invention may also be prepared using known methods. The skilled person will know that the full-length gastric cancer marker polypeptide or fragment thereof can be obtained from Thousands of I & N. ^ The door t is further prepared by using the antibody of the present invention. The polypeptide used to produce the antibody of the present invention can be partially purified from a natural source, and can also be produced by recombinant DNA techniques. For example, eDNA or one of the fragments encoding the MST1R, UCHL5, SMC4, NFYB, ppAp2c, hunger 9, uqcrb and MUC6 polypeptides can be in prokaryotic cells (eg bacteria) or eukaryotic cells (eg yeast, insect or lactation) Expression in animal cells), after which the recombinant protein can be purified and used to produce a monoclonal or polyclonal antibody preparation that specifically binds to a gastric cancer marker polypeptide used to produce the antibody. Those skilled in the art will appreciate that 'two or more different sets of monoclonal or polyclonal antibodies maximize the specificity and affinity required to achieve a desired use (eg, ELISA, immunohistochemistry) , the possibility of antibodies in vivo imaging, immunotoxin therapy). Depending on the use of the antibody, its desired activity is tested by known methods (e.g., ELISA, immunohistochemistry, immunotherapy, etc.; for further guidance on the production and testing of antibodies, see, for example, Harlow and

Lane, Antibodies:A Laboratory Manual, Cold Spring Harbor

Laboratory Press, Cold Spring Harbor, N.Y., 1988). For example, the antibody can be detected by ELISA, immunoblotting, immunohistochemical staining of a formalin-fixed gastric cancer sample or ice; After initial in vitro characterization, antibodies for therapeutic or in vivo diagnostic use are tested according to the known clinical test method of 154845.doc -85-201200594. The term "monoclonal antibody" as used herein refers to a large number of homogeneous antibodies. An antibody obtained 'that is, a population of antibodies consisting of the same antibody, except for natural mutations that may be presented in small amounts. The monoclonal antibodies described herein specifically include "chimeric" antibodies, some of which are heavy and/or light. A strand is identical (homogenous) to an antibody obtained from a particular species or to a corresponding antibody of a particular antibody type and type of antibody', while the remaining strand is associated with an antibody obtained from another species or a corresponding sequence of antibodies belonging to a particular antibody type and subtype and Fragments of these antibodies are identical (homogeneous) as long as they exhibit the expected antagonistic activity (US Pat. No. 4,816,567). The monoclonal antibodies of the invention may be made using the hybridoma method. In the hybridoma method, a mouse or other appropriate host animal, usually with an immunological preparation, elicits the production or production of an antibody that will specifically bind to the immunological preparation. Alternatively, lymphocytes can be immunized in vitro. Monoclonal antibodies can also be made by recombinant DNA methods, as described in U.S. Patent No. 4,816,567. The DNA encoding the monoclonal antibody of the present invention can be easily isolated and sequenced using conventional procedures (e.g., by using an oligonucleotide probe that specifically binds to a gene encoding a heavy chain and a light chain of a murine antibody). In vitro methods are also suitable for the preparation of monovalent antibodies. Fragments of antibodies to produce antibodies, particularly Fab fragments, can be accomplished using conventional techniques known in the art. For example, digestion can be accomplished by using papain. Examples of papain digestion are described in WO 94/29348 and U.S. Patent 4,342,566, issued December 22, 1994. The papaya egg of the antibody -86 - 154845.doc 8 201200594 White enzyme digestion usually produces two identical antigen-binding fragments, called (iv) slice slaves (each fragment has an antigen binding site) and residual Fe fragments. Pepsin treatment produces a fragment that has two antigen-binding sites and still has the ability to cross-link antigen. An antibody fragment, whether or not it is attached to another sequence, may include insertion, deletion, substitution, or other selective modification of a particular region or particular amino acid residue, provided that the activity of the fragment is unmodified or antibody sheet k Significant changes or damage compared to cockroaches. These modifications provide additional properties such as deletion/addition of amino acids that bind to disulfide bonds to increase their biological life and alter their secretory properties. In any case, the antibody fragment must possess biologically active properties such as binding activity, binding of the binding domain, and the like. The functional or active region of an antibody can be determined by gene mutations in a particular region of the protein, subsequent expression and testing of the expressed polypeptide. These methods are well known to those skilled in the art and may include mutations at specific site genes of nucleic acids encoding antibody fragments. The antibody of the present invention may further comprise a humanized antibody or a human antibody. Humanized forms of non-human (eg, murine) antibodies are chimeric antibody immunoglobulins, immunoglobulin bonds or fragments thereof (eg, Fv, Fab, Fab, or other antigen-binding sequences of antibodies) The smallest sequence obtained in human immunoglobulin. Humanized antibodies include human immunoglobulins (receptor antibodies) in which residues from the complementarity determining regions (CDRs) of the genus are derived from non-human species (donor antibodies) (eg, having a small specificity, affinity, and ability) The residues of the CDRs of the murine, rat or rabbit) are substituted. In some cases, the Fv framework (FR) residues of human immunoglobulins are replaced by corresponding non-human residues. Humanized antibody can be 154845.doc •87· 201200594 can be used as a spoon: not a receptor antibody, nor is it found in cDR or framework sequences, as well as earthworms, humanized antibodies will include almost all of at least one Hanging is a variable domain in which all or nearly all of the CDR region sentences correspond to regions of non-human immunoglobulin and all or nearly all of the regions are regions of the same sequence of human immunoglobulins. Ideally, the humanized antibody will also include at least a portion of the immunoglobulin constant region (Fc) that is normally part of the constant region of the human immunoglobulin. Methods for humanizing non-human antibodies are well known in the art. Generally, humanized antibodies have one or more amino acid residues introduced from a non-human source. These non-human amino acid residues are often referred to as "input" residues and are usually obtained from the input "variable domain". Humanization can be accomplished essentially by replacing the rodent CDR or CDR sequences with the corresponding human antibody sequences. Thus, such "humanized" antibodies are chimeric antibodies (U.S. Patent No. 16,567), in which much less than the intact human variable domain is replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some 1-11 residues are substituted with residues from analogous sites in rodent antibodies. A transgenic animal (e.g., a mouse) capable of producing a complete human antibody when the endogenous immunoglobulin is deleted after immunization can be used. For example, it is described that homozygous deletion of the antibody heavy chain joining region gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. The transfer of the human germline immunoglobulin gene array in such a mutant mouse will result in the production of human antibodies following antigen challenge. Human antibodies can also be produced in phage display libraries. The antibody of the present invention is preferably administered to a subject in the form of a pharmaceutically acceptable carrier. I54845.doc • 88 - 201200594. Medicinal. Solution Generally, an appropriate amount of a pharmaceutically acceptable salt is used in the preparation such that the pH of the physiologically saline, Ringer's solution and the glucose solution of the preparation is preferably from about 5 to 8', more preferably from about 7 to about 75. Further, the carrier further comprises a sustained release preparation' such as a solid hydrophobic polymer semipermeable matrix containing an antibody, wherein the matrix is in the form of a tangible article such as a ruthenium film, a liposome or a microparticle. It is well known to those skilled in the art that it may be more preferred to use only a small amount of the carrier, depending on, for example, the route of administration and concentration of the antibody. The antibody can be administered to a subject, patient or cell by injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular) or by other means such as infusion to ensure that it is delivered to the blood in an effective form. These antibodies can also be administered by intratumoral or peritumoral routes to exert a local and systemic therapeutic effect. Local or intravenous injection is preferred. The effective dosage and schedule of antibody administration can be determined empirically and it is within the skill of the art to make such determinations. Those skilled in the art will appreciate that the amount of antibody that must be administered will vary depending on factors such as the subject of the antibody, the route of administration, the antibody used, and the particular type of drug being used. The usual daily dose of the antibody used alone may range from about 1 pg/kg to at most 100 mg/kg body weight or more' depending on the above factors. After administration of an antibody to treat gastric cancer, the efficacy of the therapeutic antibody can be assessed by various methods well known to the skilled artisan. For example, the size, number, and/or distribution of gastric cancer in a subject undergoing treatment can be monitored using standard tumor imaging techniques. An antibody administered for treatment can prevent tumor growth, cause tumor shrinkage, and/or prevent the development of new tumors as compared with the course of administration of the antibody. Such an antibody is an antibody effective for treating gastric cancer. 154845.doc -89- 201200594 Because of proteins ABL1, ADAM10, AHR, CCND2, CDC6, CDK1, CEACAM1, CEACAM5, CEACAM6, CEACAM6, COL6A3, EIF2S3, LOC255308, EPHA2, ERBB2, ERBB3, F2R, FAP, HMMR, HSP90B1, IGF2BP3 , ITGB4, KIF2C, KRAS, LAMC2, LCN2, MET, MMP11, MMP12, MMP3, MST1R, NUF2, 0LFM4, PR0M1, RRM2, THY1, TMPRSS4, TOP2A, TSPAN1, WNT5A, HIF1A, and PTK2 show gastric cancer compared with normal tissues At least one subset of the tissue is highly expressed, so inhibition of its performance or activity can be incorporated into any therapeutic strategy for treating or preventing gastric cancer. The principle of antisense therapy is based on the hypothesis that sequence specific inhibition of gene expression (by transcription or translation) may be achieved by hybridization between genomic DNA or mRNA and complementary antisense species. This hybridization of nucleic acid duplex interferes with the transcription of the target tumor antigen encoding genomic DNA, or the processing/transportation/translation and/or stability of the target tumor antigen mRNA. Antisense nucleic acids can be delivered in a variety of ways. For example, an antisense oligonucleotide or antisense RNA can be administered directly (e. g., by intravenous injection) to a subject in a manner that allows tumor cells to be taken up. Alternatively, a viral or plasmid vector encoding an antisense RNA (or RNA fragment) can be introduced into cells in vivo. Antisense effects can also be induced by sense sequences; however, the extent of phenotypic changes varies widely. Phenotypic changes induced by effective antisense therapy can be assessed based on, for example, changes in target mRNA levels, target protein levels, and/or target protein activity levels. In a specific embodiment, the antisense gene therapy can inhibit the function of gastric cancer markers by directly administering an antisense gastric cancer marker RNA to a subject. 154845.doc • 90· 201200594 Yes. Tumor marker antisense RNA can be made and isolated by any standard technique, but the easiest method of manufacture is to use in vitro transcription of tumor marker antisense cDNA using a highly efficient promoter (e. g., a T7 promoter). The administration of the tumor marker antisense RNA to the cells can be carried out by any of the methods of direct administration of the nucleic acids described below. Alternative strategies for inhibition of MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 using gene therapy include anti-MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 antibodies or anti-MST1R, UCHL5, Intracellular expression of a portion of SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 antibodies. For example, a gene (or gene fragment) encoding a monoclonal antibody that specifically binds to a MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 polypeptide and inhibits its biological activity is specific (eg, tissue specific or tumor) The specificity gene regulatory sequences are placed under transcriptional control within the nucleic acid expression vector. The vector is then administered to the subject for absorption by gastric cancer cells or other cells, which then secrete anti-MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB or MUC6 antibodies and block MST1R, UCHL5, SMC4, NFYB , PPAP2C, AVL9, UQCRB and MUC6 polymorphic biological activity. Preferably, MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 are present on the extracellular surface of gastric cancer cells. In the above method, which comprises administering and absorbing exogenous DNA into the cells of the subject (ie, (ie, transduction or transfection), the core of the invention 154845.doc-91 201200594 acid The naked DNA form or nucleic acid can be delivered to the cell in a vector to inhibit expression of a gastric cancer marker protein. The vector can be a commercially available preparation, such as an adenoviral vector (Quantum Biotech, Laval, Quebec, Canada). The nucleic acid or vector can be delivered to the cell by a variety of mechanisms. For example, commercially available liposomes such as: LIPOFECTIN, LIPOFECTAMINE (GIBCO-25 BRL, Gaithersburg, Md.), SUPERFECT (Qiagen, Hilden, Germany) can be used. And TRANSFECTAM (Promega Biotec, Madison, Wis.) and other liposomes developed according to standard procedures in the art, delivered by these liposomes. Furthermore, the nucleic acids or vectors of the invention can be delivered by electroporation in vivo, which can be Genetronics (San Diego, Calif.) was acquired and delivered by the SONOPORATION machine (ImaRx Pharmaceuticals, Tucson, Arizona). For example, the vector can be delivered by a viral system, such as a retroviral vector system that can coat the recombinant retroviral genome. The recombinant retrovirus can be used for infection, thereby transmitting to inhibit MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB. Or an infected cell antisense nucleic acid expressed by MUC6. Of course, the accurate introduction of the altered nucleic acid into mammalian cell cells is not limited to the use of retroviral vectors. There are a wide variety of other techniques available for this procedure, including Adenoviral vectors, adeno-associated virus (AAV) vectors, lentiviral vectors, pseudotyped retroviral vectors. Physical transduction techniques such as liposome delivery and receptor mediated and other endocytic mechanisms can also be used. It can be used in combination with any of these techniques or other commonly used gene transfer methods. 154845.doc -92· 8 201200594 This antibody can also be used in in vivo diagnostic assays. In general, antibodies are labeled with radionuclides (eg, lnln, 99Tc, 14C, 134, 3H, 32 p bite 35 S) 'This allows immunosplitting scanning to localize tumors. In the embodiment, the antibody or fragment binds to the extracellular domain of two or more MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 targets, and the affinity value (Kd) is less than 1 μμ. Diagnostic antibodies can be labeled by a variety of imaging methods using probes suitable for detection. Probe detection methods include, but are not limited to, fluorescence, light, co-focus, and electron microscopy methods; magnetic resonance imaging and spectroscopy techniques; fluoroscopy, computed tomography, and positron emission tomography. Suitable probes include, but are not limited to, 'luciferin, rhodamine, eosin, and other glory groups, radioisotopes, gold, barium, and other rare earths, paramagnetic, fluorine- 18, and other positron-emitting radionuclides. Furthermore, the probes may be dual or multifunctional and can be detected by more than one of the above methods. These antibodies can be labeled directly or indirectly with the probes described. Attachment of antibody probes includes covalent attachment of probes, fusion of probes into antibodies, and covalent attachment of chelating compounds to bind probes, as well as other methods well known in the art. For immunohistochemical methods, disease tissue samples may be fresh or cold-reduced or may be embedded in sarcophagus and preservatives such as formalin. The fixed or embedded sections include samples that are contacted with a labeled primary antibody and a secondary antibody, wherein the antibody is used to detect the expression of MST1R, UCHL5, SMC4, sputum, PPAP2C, AVL9, UQCRB, and MUC6 proteins in situ. The present invention provides a form comprising a sequence selected from the group consisting of SEQ m阙: 154845.doc-93-201200594 SEQ ID NO: 95 or having SEQ ID NO: 1 to SEQ ID NO: 95 A variant of 85%, preferably 90% and more preferably 96% homology, or a variant thereof which induces T cell to react with the peptide. The peptides of the present invention have the ability to bind to major histocompatibility complex (mhc) class I molecules. In the present invention, the term "homology" refers to the degree of identity between two amino acid sequences, such as a peptide or polypeptide sequence. The "homologous" as described above is determined by comparing two sequences adjusted under ideal conditions with the sequences to be compared. Here, the sequence to be compared may be added or deleted (e.g., 'void, etc.) in the optimal alignment of the two sequences. Such sequence homology can be calculated by creating an arrangement using an algorithm such as ClustalW. General sequence analysis software can also be used, more specifically Vect〇r NTI, GENETYX or analysis tools provided by public databases. One skilled in the art will be able to assess whether a particular peptide variant-induced T cell can interact with the peptide itself (Fong et al. 8809-14); (Appay et al. 1805-14; Colombetti et al. 2730-38 Zaremba et al. 4570-77). The "variant" of a given amino acid sequence by the inventors indicates that the side chain of one or more amino acid residues or the like is altered by being substituted by a side chain or other side bond of another natural amino acid residue. Thus, such a peptide It is still possible to bind to the HLA molecule in substantially the same manner as the peptide containing the given amino acid sequence of SEQ ID NOS: 1 to 33. For example, a peptide may be modified to at least maintain (if not elevated) its ability to interact and bind to binding pockets of suitable MHC molecules such as HLA-A or -DR, and at least maintain (if not elevated) I54845.doc • 94- 201200594 It can be combined with the TCR that starts the CTL. These CTLs can then react with cells and killer cells, which express polymorphism (which contains the natural amino acid sequence of the homologous peptides defined in the present invention). As in the scientific literature (Rammensee, Bachmann, and

As described in Stevanovic and the database (Rammensee et al. 213-19), certain sites of the HLA-A binding are usually tin residues, which form a core commensurate with the binding motif of the HL A binding groove. A sequence whose definition is determined by the polarity, electrophysical, hydrophobic and spatial properties of the polypeptide chains that make up the binding groove. Thus, one skilled in the art will be able to modify the amino acid sequences set forth in SEQ ID Nos: 1 to 95 by maintaining known anchor residues and to determine whether these variants retain the ability to bind to MHC class I or class II molecules. The variants of the invention retain the ability to bind to the TCR that initiates the CTL, which in turn can react with cells that express a polypeptide comprising a native amino acid sequence of a homologous peptide as defined herein and kill the cells. These amino acid residues that do not substantially interact with the T cell receptor can be modified by substituting another amino acid that hardly affects the T cell response and does not interfere with binding to the relevant MHC. Thus, in addition to particular limiting conditions, the peptides of the present invention may be any peptide comprising a given amino acid sequence or portion or variant thereof (the term used by the inventors includes oligopeptides or polypeptides). 154845.doc 95· 201200594 Table 3: Peptide variants and motifs according to SEQ ID ΝΟ: 1 to 33

Position 1 2 3 4 5 6 7 8 9 10 CDC2-001 Peptide code LYQILQGIVF SEQ ID 1 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 ASPM-002 Peptide code SYNPLWLRI SEQ ID 2 Variant FLFFLFF Position 1 2 3 4 5 6 7 8 9 UCHL5-001 Peptide code NYLPFI Μ Ε L SEQ ID 3 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 MET-006 Peptide code SYIDVL Ρ F SEQ ID 4 Variant FLIFFFI Position 1 2 3 4 5 6 7 8 9 PROM-001 Peptide code SYIIDPL Ν L SE〇ID 5 Variant FF 154845.doc -96- 8 201200594

IFFFI position 1 2 3 4 5 6 7 8 9 10 MMPl 1-001 Peptide code VWSDV Τ Ρ L Τ F SEQ ID 6 Variant Υ FLI Υ L Υ IFLFI Position 1 2 3 4 5 6 7 8 9 MST1R-001 Peptide code N Υ LL Υ VS Ν F SEQ ID 7 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 NFYB-001 Peptide code V Υ Τ Τ S Υ QQI SEQ ID 8 Variant FLFFLFF Position 1 2 3 4 5 6 7 8 9 SMC4-001 Peptide Code Υ Κ Ρ Ρ Τ Ρ L Υ F SEQ ID 9 Variant FLIFLFI 154845.doc -97- 201200594

Position 1 2 3 4 5 6 7 8 9 10 UQCRB-001 Peptide code YYNAAGFNKL SEQ ID 10 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 PPAP2C-001 Peptide code AYLVYTDRL SEQ ID 11 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 AVL9-001 Peptide code FYISPVNKL SEQ ID 12 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 NUF2-001 Peptide code VYGIRLEHF SEQ ID 13 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 ABL1 -001 Peptide code TYNNLLDYL SEQ ID 14 Variant FFIFF 154845.doc -98- 201200594

FI position 1 2 3 4 5 6 7 8 9 MUC-006 Peptide code NYEETFP Η I SEQ ID 15 Variant FFLFFFL Position 1 2 3 4 5 6 7 8 9 ASPM-001 Peptide code RYLWATV Τ I SEQ ID 16 Variant FFLFFFL position 1 2 3 4 5 6 7 8 9 EPHA2-005 Peptide code VYFSKSEQL SEQ ID 17 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 MMP3-001 Peptide code VFIFKGNQF SE〇ID 18 Variant YLIYLYI Position 1 2 3 4 5 6 7 8 9 NUF2-002 Peptide code RFLSGIINF SEQ ID 19 Variant YLI 154845.doc -99· 201200594

YLYI position 1 2 3 4 5 6 7 8 9 PLK4-001 peptide code QYASRFVQL SEQ ID 20 variant FFIFFFI position 1 2 3 4 5 6 7 8 9 ATAD2-002 peptide code KYLTVKDYL SEQ ID 21 variant FFIFFFI position 1 2 3 4 5 6 7 8 9 COL 12A1-001 Peptide code VYNPTPNSL SEQ ID 22 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 COL6A3-001 Peptide code SYLQAANAL SEQ ID 23 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 FANCI-001 Peptide Code FYQPKIQQF SEQ ID 24 Variant FL 154845.doc •100- 8 201200594

IFLFI position 1 2 3 4 5 6 7 8 9 RSPl 1-001 Peptide code YYKNIGLGF SEQ ID 25 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 ATAD2-001 Peptide code AYAIIKEEL SEQ ID 26 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 ATAD2-003 Peptide code LYPEVFEKF SEQ ID 27 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 10 HSP90B1-001 Peptide code KYNDTFWKEF SEQ ID 28 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 10 SIAH2-001 Peptide code VFDTAIAHLF SEQ ID 29 Variant Y 154845.doc -101 - 201200594

LIYLYI position 1 2 3 4 5 6 7 8 9 SLC6A6-001 peptide code VYPNWAIGL SEQ ID 30 variant FFIFFFI position 1 2 3 4 5 6 7 8 9 IQGAP3-001 peptide code VYKVVGNLL SEQ ID 31 variant FFIFFFI position 1 2 3 4 5 6 7 8 9 ERBB3-001 Peptide code VYIEKNDKL SEQ ID 32 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 10 KIF2C-001 Peptide code IYNGKLFDLL SEQ ID 33 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 10 CDC2-001 Peptide code LYQILQGIVF I54845.doc -102- 201200594 SEQ ID 1 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 ASPM-002 Peptide code SYNPLWLRI SEQ ID 2 Variant FL FFLFF position 1 2 3 4 5 6 7 8 9 UCHL5-001 Peptide code NYLPFI Μ Ε L SEQ ID 3 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 MET-006 Peptide code SYIDVL Ρ Ε F SEQ ID 4 Variant FLIFFFI position 1 2 3 4 5 6 7 8 9 PROM-001 Shape code SYIIDPL Ν L SEQ ID 5 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 10 154845.doc -103- 201200594

MMPl 1-001 Peptide code VWSDV Τ Ρ L Τ F SEQ ID 6 Variant Υ FLI Υ L Υ IFLFI Position 1 2 3 4 5 6 7 8 9 MST1R-001 Peptide code N Υ LL Υ VS Ν F SEQ ID 7 Variant FLIFLFI position 1 2 3 4 5 6 7 8 9 NFYB-001 Peptide code V Υ Τ Τ S Υ QQI SEQ ID 8 Variant FLFFLFF Position 1 2 3 4 5 6 7 8 9 SMC4-001 Peptide code Η Κ Κ Ρ Τ Ρ L Υ F SEQ ID 9 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 1 0 UQCRB-001 Peptide Code Υ Υ Ν AAGF Ν Κ L SEQ ID 10 Variant F 154845.doc •104- 8 201200594

FIFFFI position 1 2 3 4 5 6 7 8 9 PPAP2C-001 Peptide code AYLVYTDRL SEQ ID 11 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 AVL9-001 Peptide code FYISPVNKL SEQ ID 12 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 NUF2-001 Peptide code VYGIRLE Η F SEQ ID 13 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 ABL1-001 Peptide code TYGNLLD Υ L SEQ ID 14 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 MUC-006 Peptide code NYEETFP Η I 154845.doc •105- 201200594 SEQ ID 15 Variant FFLFFFL Position 1 2 3 4 5 6 7 8 9 ASPM-001 Peptide code RYLWATVTI SEQ ID 16 Variant FF LFFFL position 1 2 3 4 5 6 7 8 9 EPHA2-005 Shape code VYFSKSEQL SEQ ID 17 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 MMP3-001 Shape code VFIFKGNQF SEQ ID 18 Variant YLIYLYI Position 1 2 3 4 5 6 7 8 9 NUF2-002 Peptide code RFLSGIINF SEQ ID 19 Variant YLIYLYI Position 1 2 3 4 5 6 7 8 9 154845.doc •106- 8 201200594

PLK4-001 Peptide code QYASRFVQL SEQ ID 20 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 ATAD2-002 Peptide code KYLTVKDYL SEQ ID 21 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 COL12A1-001 Peptide code VYNPTPNSL SEQ ID 22 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 COL6A3-001 Peptide Code SYLQAANAL SEQ ID 23 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 FANCI-001 Peptide Code FYQPKIQQF SEQ ID 24 Variant FLIFLFI 154845.doc -107- 201200594

Position 1 2 3 4 5 6 7 8 9 RSPl 1-001 Peptide code YYKNIGLGF SEQ ID 25 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 ATAD2-001 Peptide code AYAIIKEEL SEQ ID 26 Variant FFIFFFI Position 1 2 3 4 5 6 7 8 9 ATAD2-003 Peptide code LYPEVFEKF SEQ ID 27 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 1 0 HSP90B1-001 Peptide code KYNDTFWKEF SEQ ID 28 Variant FLIFLFI Position 1 2 3 4 5 6 7 8 9 1 0 SIAH2-001 Peptide code VFDTAIAHLF SEQ ID 29 Variant YLI 154845.doc -108- 8 201200594

SLC6A6-001 SEQ ID 30 ^-- YL ^----- YI '-- Position 1 2 3 4 5 6 7 8 9 VYPNWAIGL Variant FFIFFFI IQGAP3-001 — pay f 1 2 3 4 5 6 7 8 9 Peptide Code VYKVV Γτ NLL SEQ ID 31 Variant F — FI — FFFI ERBB3-001 SEQ ID 32 Position 1 2 3 4 5 6 7 8 9 Exhaustion VYIEK Ν DKL Variant Π F ----- FI — FFFI Position 1 2 3 4 5 6 7 8 9 1 0 KIF2C-001 Peptide code IYNGKLFDLL SEQ ID 33 Variant F 〜 I — FFF Longer peptides may also be suitable. MHC class I epitopes (usually 8 to 11 amino acids in length) may also be produced by peptides from a county with a longer peptide or a protein containing the actual epitope 154845.doc -109. 201200594 The residue having an actual epitope on both sides is preferably a residue which does not affect the proteolytic cleavage required to expose the actual epitope during processing. Thus, the present invention also proposes peptides and variants of MHC class I epitopes, wherein the total length of the peptide or antibody is from 8 to 100, preferably from 8 to 30, most preferably from 8 to 14 (ie 8, 9' 10, 11, 12, 13, 14) oxyacids. Of course, the peptides or variants of the invention bind to human major histocompatibility complex (MHC) class I or class II molecules. Binding of the peptide or variant to the mHc complex can be tested by methods known in the art. In a particularly preferred embodiment of the invention, the peptide consists of or consists essentially of the amino acids according to SEQ ID ΝΟ:1 to SEQ ID NO:95. "Consisting essentially of" means a peptide of the present invention, in addition to being constituted according to any of SEq id 1:1 to SEQ ID NO: 95 or a variant thereof, and also located at other N- and/or C-terminal extensions. Amino acids, and they do not necessarily form peptides that are epitopes of MHC molecules. However, these extension regions have an important effect on the efficient introduction of the peptide of the present invention into cells. In one embodiment of the present invention, the peptide is a fusion protein comprising 8 N N_ from the HBI-DR antigen-associated invariant chain (p33 'hereinafter referred to as "Π") from NCBI, GenBank Accession No. 497. Amino acid and the like. Furthermore, the peptide or variant may be further modified to increase stability and/or bind to the MHC molecule to elicit a stronger immune response. Such optimization methods for peptide sequences are well known in the art and include, for example, the introduction of trans-peptide bonds and non-peptide bonds. In the trans-peptide-bonded amino acid, the peptide CO-NH-) is not linked to its residue, but its peptide bond is reversed. This reverse-reverse mimetic peptide (retr〇_invers〇I54845.doc •110· 8 201200594 peptidomimetics) can be prepared by methods known in the art, for example:

The method described by Meziere et al., J. Immunol. ((1997) J. Immun〇i. 159, 3230-3237) is incorporated herein by reference. This method involves the preparation of a peptidomimetic comprising a change in the backbone, but not the side chain. ^^"^ et al. (1997) showed that these analog peptides favor mhc binding and helper T cell responses. Reverse reversed peptides that replace CO-NH peptide bonds with NH-CO bonds have greatly improved Hydrolysis resistance. Non-peptide bonds are _CH2-NH, -CH2S-, -CH2CH2-, _CH=CH-, _COCH2-, -CH(OH)CH2- and -CH2SO-, etc. The polypeptide is proposed in US Pat. A non-solid phase synthesis of a non-peptide bond (-CHz-NH) in a chain involving a polypeptide synthesized according to standard procedures and a non-peptide bond synthesized by the interaction of an aminoaldehyde with a NaCNBH3-containing amino acid. Peptides can be synthesized with their amino and/or other chemical groups at the terminal end of the group to increase the stability, bioavailability, and/or affinity of the peptide, etc. For example, hydrophobic groups such as 'benzyloxycarbonyl, tanshinyl, or tertiary A butoxycarbonyl group can be added to the amino terminus of the peptide. Similarly, an ethionyl group or a 9-mole oxygen group may be located at the amino terminus of the peptide. Further, a hydrophobic group, a t-butoxy group or an amino group may be added to the peptide. In addition, all peptides in the present invention may be modified by synthesis. It is possible to change its spatial configuration. For example, it is possible to use the right-handed body of one or more amino acid residues of these peptides, usually not its left-handed body. Further, at least one amino acid residue of the peptide of the present invention can be known. Substitution of a non-natural amino acid residue. Such changes may help to increase the stability, bioavailability and/or binding of the peptides of the invention. 154845.doc 201200594 Similarly, the peptides or variants of the invention may be synthesized The peptide is chemically modified by a reaction of a specific oxyacid before or after the peptide. Examples of such modifications are well known in the art, for example, "Chemical Reagents for Pr〇tein Modification" by R. Lundblad (3rd ed. CRC Press, 2005) is incorporated by reference in its entirety. Although the amino-chemical modification method is not limited, it includes, but is not limited to, modification by thiolation, thiolation, Lysine pyridylation, reductive alkylation, 2,4,6-trinitrobenzenesulfonic acid (TNBS) trinitrophenylated amino group, by oxidation of cysteine percarboxylic acid to sulfo group C Acid and amino group modification of carboxyl group and sulfhydryl group, formation of a volatile derivative, formation of a mixed disulfide compound with other mercapto compounds, reaction with maleimide, carboxylation with iodoacetic acid or iodoacetamide, Cyanide is cyanide at alkaline pH. In this regard, 'Technicians refer to Current Protocols In Protein Science' (Eds. Coligan et al. (J〇hn Wiley & Sons NY 1995-2000) A broad range of methods related to chemical modification of proteins as described in Chapter 15. Simplified S's modified amino acid residues of the protein are often formed based on the reaction of the adjacent two prison compounds (such as benzoquinone formaldehyde, 2,3-butanedione, and 1,2-enephthalenedione). Compound. Another example is the reaction of pyruvic aldehyde with an arginine residue. Cysteine can be modified without modification with nucleophilic sites such as lysine and histidine. Therefore, a large number of reagents can be modified with cysteine. The company's website, such as Sigma-Aldrich (http://www.sigma-aldrich.com), contains information on specific reagents. Selective reduction of disulfide bonds in proteins is also common. Disulfide bonds can form and oxidize in biopharmaceutical heat treatment. 154845.doc 112 201200594 Woodward's reagent K can be used to modify specific glutamic acid residues β N-(3--f-aminopropyl)-Ν'-ethyl-carbodiimide can be used to form lysine Intramolecular crosslinking of residues and glutamic acid residues. For example, diethyl pyrocarbonate is a reagent that modifies a histidine residue. Histidine can also be modified using 4-hydroxy-2-nonenal. The reaction of a lysine residue with other hydrazine-amino groups, for example, facilitates binding of the peptide to the surface or cross-linking of the protein/peptide. Lysine poly is the attachment point of poly(ethylene) glycol and is also the major modification site for protein glycosylation. The methionine residue of the protein can be modified by iodoacetamide, bromoethylamine, amiamine tau, and the like. Tetranitrodecane and oxime-ethenyl imidazole can be used for the modification of tyrosine residues. The cross-linking formed by di-tyrosine can be used to complete the modification of β-tryptophan by hydrogen peroxide/copper ions. In recent studies using β-bromoarene quinone imine, 2-hydroxy-5-nitrobenzyl bromide or 3-bromo-3-methyl-2-(2-nitrophenylhydrazino)_3Η-吲哚 (BPNS-skatole). § Cross-linking of proteins with valeric acid, polyethylene glycol diacrylate and formic acid For the preparation of hydrogels, successful modification of therapeutic proteins and peptides containing polyethylene glycol often prolongs the half-life of the loop. Allergen chemical modifications for immunotherapy are often achieved by aminoguanidine of potassium cyanate. A peptide or variant 'where the peptide is modified or contains a non-peptide bond, preferably an embodiment of the invention. In general, peptides and variants (at least peptide linkages between amino acid residues) can be synthesized using the solid phase peptides of Lu et al. (1981) and the references listed herein to synthesize Fmoc-polyamide. The pattern is synthesized. The methoxycarbonyl (Fmoc) group provides temporary protection for the N-amino group. Repeated cleavage of a protecting group that is highly sensitive to this domain in 20% dimethyl acridine in guanamine using N,N-dimethyl 154845.doc •113·201200594. Due to their butyl ether (in the case of serine threonine and sulphate), butyl ester (in the case of glutamic acid and aspartic acid), tert-butoxycarbonyl derivative (in lysine) In the case of acid and histidine), a trityl derivative (in the case of cysteine) and a 4-decyloxy-2,3,6-trimethylbenzene hydrazino derivative (in the case of acid and histidine) In the case of arginine, the side chain function may be protected. As long as the indoleamine and asparagine are C-terminal residues, the side bond amino functional protection is carried out by the 4,4'-dimethoxydiphenyl group. The solid phase support is based on a polydimercapto acrylamide polymer consisting of three monomeric dimercapto acrylamide (skeletal monomer), bis propylene ethylene diamine (crosslinking agent) and N-propylene hydrazine Methyl creatinine (functional agent) is composed. The resin-linking agent used is an acid-sensitive 4-hydroxydecylphenoxyacetic acid derivative. All amino acid derivatives are added as their pre-formed symmetrical anhydride derivatives, except for aspartame and hydrazine amines, which use reversed N,N-dicyclohexylcarbodiimide via benzotriazole Joined by the coupling program. All coupling and deprotection reactions were monitored using Bp diketone, benzoic acid or is〇tjn test procedures. After completion of the synthesis, the peptide was cleaved from a resin support accompanied by removal of the side chain protecting group with a concentration of 95% trifluoroacetic acid containing a 50% scavenger mixture. Commonly used scavenger mixtures include ethanedithiol, phenol, anisole and water, with the exact choice based on the amino acid composition of the synthetic peptide. In addition, solid phase and liquid phase methods are possible in combination with the use of a pair (see, for example, Bruckdorfer et al. Trifluoroacetic acid is evaporated in vacuo and subsequently removed by titration with diethyl ether carrying the crude peptide. Extraction procedure (after lyophilization of the aqueous phase, the procedure 154845.doc -114-201200594 peptides without a scavenger mixture) removes any existing scavenger mixture. The synthase can be obtained from Calbiochem-Novabiochem (UK) Company (NG7 2QJ, UK). Purification can be carried out by any one or combination of the following techniques, such as: recrystallization, size exclusion chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and (usually) reversed phase efficiency Liquid chromatography (eg using acetonitrile/water gradient separation) Peptide analysis can be performed using the following methods: thin layer chromatography, electrophoresis, in particular, capillary electrophoresis, solid phase extraction (CSPE), reversed phase high performance liquid chromatography Chromatography, amino acid analysis after acid hydrolysis, fast atom bombardment (FAB) mass spectrometry, and MALDI, ESI-Q-TOF mass spectrometry. The invention proposes a nucleic acid (such as a polynucleotide) encoding a peptide or peptide variant of the invention. The polynucleotide may be, for example, DNA, cDNA, PNA, CNA, RNA or a combination thereof, It may be a single or a double strand, or a native or stable form of a polynucleotide (eg, a polynucleotide having a phosphorothioate backbone), and may or may not contain as long as it encodes a peptide Introns. Of course, polynucleotides can only encode peptides that incorporate natural peptide bonds and contain natural amino acid residues. Another aspect of the invention provides an expression vector that can express a polypeptide according to the invention. Acids, various methods have been developed, especially for DNA, which can be ligated by supplementing the vector with a linker end, etc. For example, a complementary homopolymer orbit can be added to the DNA fragment, after which the DNA fragment is inserted into the vector DNA. Then, the carrier and the DNA fragment are combined by gas 154845.doc 115 201200594, which is a complementary homopolymer tail, to form a recombinant DNA molecule. 3 Synthesis of one or more cleavage sites The head provides an alternative method for ligation of DNA fragments to vectors. Synthetic linkers containing various restriction endonucleases are commercially available through a variety of pipelines including from International Biotech (International Bi0techn〇i〇gies Inc, New Haven, CN , USA), the preferred method for DNA modification encoding a polypeptide of the invention is the polymerase chain reaction method employed by Saiki et al. (1988). This method can be used to introduce DNA into a suitable vector (eg, by design The cleavage site can also be used to modify the DNA in other useful methods known in the art. A poxvirus vector or an adenoviral vector is preferred if a viral vector is used. Thereafter, the DNA (or RNA in the case of a retroviral vector) may be expressed in a suitable host to produce a polypeptide comprising the peptide or variant of the present invention. Thus, a DNA encoding a peptide or variant of the invention can be used according to known techniques, and appropriately modified by the methods described herein to construct an expression vector, which can then be used to transform a suitable host cell to express and produce the polypeptide of the invention. . These methods include the methods disclosed in the following U.S. Patents: 4,440,859, 4,530,901, 4,582,800, 4,677,063, 4,678,751, 4,704,362 > 4,710,463 '4,757,006 '4,766,075^4,810,648 〇 encoding DNA containing a polypeptide of the compound of the invention (or in the case of a retroviral vector, RNA) may be added to a variety of other sequences to be introduced into a suitable host. The companion DNA will depend on the nature of the host, the way the DNA is introduced into the host, and whether it needs to remain as a free form or a combination of 154845.doc •116· 201200594. In general, DNA can be attached to an expression vector (such as a plasmid) in the appropriate orientation and in the correct expression reading frame. If necessary, the DNA may be linked to the corresponding transcriptional and translational regulatory control nucleotide sequences recognized by the desired host, although such (four) functions are generally present in the expression vector. The vector is then introduced into the host by standard methods. In general, not all hosts are transformed by the vector. Therefore, it is necessary to select transformed host cells. The selection method involves the insertion of a DNA sequence into the expression vector with any necessary control elements that encodes selectable properties (e.g., antibiotic resistance) in the transformed cell. Alternatively, a gene having such a selection property can be used on a vector which is used to cooperatively transform a desired host cell. Then, the host cell transformed with the recombinant DNA of the present invention is cultured for a sufficiently long period of time under suitable conditions as described herein, to express the peptide which can be recovered later. There are many known expression lines, including bacteria (such as Escherichia coli and Bacillus subtilis), yeast (such as yeast), filamentous fungi (such as Aspergillus), plant cells, animal cells, and insect cells. The line may preferably be a mammalian cell, such as a CHO cell from the ATCC Cell Biology Library (CeU Bi〇1〇gy Co-). A typical mammalian cell constitutive expression vector plasmid includes c M V or an SV4 〇 promoter containing a suitable poly A tail and a resistance marker (e.g., neomycin). An example is the pSVL obtained from Pharmacia (Piscataway, New Jersey USA). An inducible mammalian expression vector 154845.doc 117 An example of 201200594 is pMSG, also available from Pharmacia. Useful yeast plasmid vectors are pRS403-406 and pRS413-416' are generally available from Stratagene Cloning Systems, Inc. (La Jolla, CA 92037, USA). Plasmids pRS403, pRS404, pRS405 and pRS406 are yeast integrated plasmids (Yip) with yeast selectable markers HIS3, TRP1, LEU2 and URA3. The pRS413-416 plasmid is a yeast centromere plasmid (Yep). Vectors based on the CMV promoter (eg, from Sigma-Aldrich) provide transient or stable expression, cytoplasmic expression or secretion 'and N-terminus in different compositions of FLAG, 3xFLAG, c-mF or MATN or C-end mark. These fusion proteins can be used to detect, purify and analyze recombinant proteins. Dual-label fusion provides flexibility for detection. The potent human cytomegalovirus (CMV) promoter regulatory region allows expression levels of constituent proteins in COS cells up to 1 mg/L. For weaker cell lines, the protein level is generally less than 0.1 mg/L. The appearance of the SV40 origin of replication will result in high level of replication of DNA in SV4〇 replication-containing COS cells. For example, the CMV vector may comprise the origin of pMB1 (a derivative of pBR322) in a bacterial cell, the calcium-indolease gene for breeding ampicillin resistance in bacteria, the origin of hGH polyA and f1. The vector containing the pro-proinsulin-directed (ppT) sequence can be used to direct the secretion of the FLAG fusion protein into the culture medium for purification using anti-FLAG antibodies, resins and plates. Other vectors and expression systems for use with a variety of host cells are well known in the art. The invention also relates to a host cell transformed with the construction of a polynucleotide vector of the invention. The host cell can be either a prokaryotic cell or a eukaryotic cell. In some cases the 'bacterial cell is a preferred prokaryotic host cell, typically 154845.doc -118· 8 201200594 is an E. coli strain, for example, E. coli strain DH5 (obtained from Bethesda Research Laboratories, Inc. (Bethesda, MD, USA)) and RR1 (obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA), ATCC No. 3 1343). Preferred eukaryotic host cells include yeast, insect and mammalian cells, preferably vertebrate cells, such as cells in mouse, rat, monkey or human fibroblasts and colon cancer cell lines. Yeast host cells include YPH499, YPH500 and YPH501, and are generally available from Stratagene Cloning Systems, Inc. (La Jolla, CA 92037, USA). Preferred mammalian host cells include Chinese hamster ovary (CHO) cells as CCL61 cells in ATCC, NIH Swiss mouse embryonic cells NIH/3T3 as CRL 1658 cells in ATCC, and monkey kidney-derived COS-1 cells as CRLs in ATCC. 1650 cells and 293 cells of human embryonic kidney cells. The preferred insect cell is Sf9 cells, which can be transfected with a baculovirus expression vector. A summary of the selection of suitable host cells for expression can be found in textbooks (Paulina Baibas and Argelia Lorence, Methods in

Molecular Biology Recombinant Gene Expression, Reviews and Protocols, Part One, Second Edition, ISBN 978-1-58829-262-9) and other literature known to those skilled in the art. Transformation of a suitable host cell comprising a DNA construct of the invention can be accomplished using well-known methods, usually depending on the type of carrier used. For the transformation of prokaryotic host cells, see, for example, Cohen et al. (1972) in Proc.  Natl.  Acad.  Sci.  USA 1972, 69, 2110 and Sambrook et al. (1989), Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 154845. Doc -119- 201200594 The method used. Transformation of yeast cells is described by Sherman et al. (1986) in Methods In Yeast Genetics, A Laboratory Manual, Cold Spring Harbor, NY. The method described in Beggs (1978) Nature 275, 104-109 is also useful. For vertebrate cells, reagents such as calcium phosphate and DEAE-dextran or liposome formulation can be obtained from Stratagene Cloning Systems, Inc. or Life Technologies, Inc. (Gaithersburg, MD 20877, USA). Electroporation can also be used to transform and/or transfect cells and is well known in the art for transforming yeast cells, bacterial cells, insect cells, and vertebrate cells. Successfully transformed cells (i.e., cells containing the DNA structure of the present invention) can be identified by well-known methods such as PCR. In addition, the protein present in the supernatant can be detected using an antibody. It will be appreciated that certain host cells of the invention are useful in the preparation of peptides such as bacterial cells, yeast cells and insect cells of the invention. However, other host cells may be useful for certain treatments. For example, antigen presenting cells (e. g., dendritic cells) can be used to express the peptides of the present invention so that they can be added to the corresponding MHC molecules. Accordingly, the present invention proposes a host cell comprising the nucleic acid or expression vector of the present invention. In a preferred embodiment the host cell is an antigen presenting cell which is a dendritic cell or an antigen presenting cell. Currently, Apc containing a recombinant fusion protein containing prostate luciferase (PAP) is being studied for the treatment of prostate cancer (Sipuleucel-T) (Rini et ^ 67_74; 8 Perak al.  3089-94) 丨 丨涵. Doc . 丨2〇_ 8 201200594 The second invention of the present invention proposes a formula - a species and a variant thereof, which comprises culturing a host cell and isolating the peptide from the host cell or its culture medium. In another embodiment, the peptide, nucleic acid or expression vector of the invention is used in a medicament. For example, the form or variant thereof can be prepared as a intravenous (four) injection, subcutaneous (S. C. Injection, intradermal (i. d. Injection, abdominal cavity (i. p. Injection muscle (i. m·) Injection. A preferred method of peptide injection includes I. , Ld·, i. p. , Lm. And i v injection. The preferred method for dna injection is 丨^, i. m. , s. c,, i. p. And i, v· injection. For example, a peptide of 5 〇 5, preferably 125 to 500, or DNA is administered, depending on the particular peptide or DNA. The above range of agents was successfully used in previous trials (Brunsvig al.  1553-64; Staehler et al. ). Another aspect of the invention includes a method of producing activated T cells in vitro - the method comprising in vitro linking T cells to antigen-loaded human MHC molecules - these molecules are expressed on the surface of a suitable antigen presenting cell for a sufficient period of time The T cell is thereby initiated in an antigen-specific manner, wherein the antigen is a peptide according to the invention. Preferably, a sufficient amount of antigen is used with the antigen presenting cells. Preferably, the TAP peptide transporter of the mammalian cell is deficient or has a decreased level or decreased function. Suitable cells lacking the TAP peptide transport vector include T2, RMA-S and Drosophila cells. TAP is a transposome that is involved in antigen processing. The defective cell line T2 loaded by the human peptide belongs to the American Type Culture Collection (ATCC, 12301 Parklawn Drive, Rockville, Maryland 20852 j 154845. Doc-121 - 201200594 USA) catalog number CRL1992; Drosophila cell line Schneider No. 2 strain ATCC catalog CRL 19863; mouse RMA-S cell strain Karre et al. described in 1985. Preferably, the host cell does not substantially express an MHC class I molecule prior to transfection. The stimulatory factor cells are also preferably molecules which express an important role in T cell costimulatory signals' such as B7. 1, B7. 2. Any of the molecules of ICAM-1 and LFA3. Nucleic acid sequences of a large number of MHC class I molecules and costimulatory molecules are publicly available from the GenBank and EMBL databases. When an MHC class I epitope is used as an antigen, the tau cell is a CD8 positive CTL. If the antigen presenting cell is transfected to express the epitope, the preferred cell comprises an expression vector which is capable of expressing the SEQ ID ΝΟ: 1 to SEQ ID NO: 95 peptide or variant amino acid sequence thereof. Other methods can be used to generate CTL in vitro. For example, a method described by Peoples et al. (1995) and a method of generating CTL using autologous tumor infiltrating lymphocytes by Kawakami et al. (1992) can be used. Plebanski et al. (1995) used CTLs derived from autologous peripheral blood lymphocytes (Plb). Jochmus et al. (1997) describe the treatment of dendritic cells with peptides or polypeptides or by autologous CTLs by infection with recombinant viruses. Hill et al. (1995) and Jerome et al. (1993) used B cells to make autologous CTLs. In addition, macrophages pulsed with peptides or polypeptides or infected with recombinant viruses can be used to formulate autologous CTLs. Walter et al., in 2003, describe the in vitro initiation of T cells by the use of artificial antigen-presenting cells (aAPC), which is also a suitable method for generating T cells that act on selected peptides. In this study, according to biotin: I54845. Doc -122- 8 201200594 Streptomycin biochemical method generates aAPC by coupling a preformed MHC:peptide complex to polystyrene particles (microspheres). This system enables precise adjustment of the MHC density on aApc, which allows for the efficient induction of high or low affinity high antigen-specific butyl cell responses in blood samples. In addition to the MHC:peptide complex, aAPC should also carry other proteins containing costimulatory activity, such as anti-CD28 antibodies coupled to the surface. Moreover, such aAPC-based systems often require the addition of an appropriate solubility factor, such as a cytokine such as interleukin-12. Tau cells can also be produced using allogeneic cells, and a method is described in detail in WO 97/26328, herein incorporated by reference. For example, in addition to Drosophila cells and T2 cells, other cells can be used to present peptides, such as CH〇 cells, baculovirus-infected insect cells, bacteria, yeast, and target cells infected with vaccinia. In addition, plant viruses can also be used (for example, see 卩 ^ et al. (1994) for the development of cowpea mosaic virus as a rlj production system for the presentation of foreign peptides. The activated T cells directly target the peptides of the present invention. Therefore, it is helpful for treatment. Therefore, another aspect of the present invention provides activating T cell produced by the aforementioned method of the present invention. The activated tau cell prepared as described above will selectively recognize abnormal expression including SEQ ID NO. A cell having a polypeptide of 1 to 95 amino acid sequence. Preferably, the T cell recognizes the cell by interacting (e.g., 'binding') with its TCR containing the hlA/peptide complex. T cells are useful in killing a cell-free method in a patient. A cell whose target cell aberrantly expresses a polypeptide comprising the amino acid sequence of the present invention. Such a patient is administered an effective amount of activating T cell. Doc • 123- 201200594 The patient's tau cells may be derived from the patient and initiated as described above (ie, they are autologous sputum cells). Alternatively, the sputum cell is not from the patient but from another person. Of course, it is preferred that the donor be a healthy person. The inventor's use of "healthy individual" means that a person is generally in good condition, preferably an immune system, and more preferably is free of any disease that can be easily tested or detected. According to the present invention, the in vivo target cells of CD8-positive sputum cells may be tumor cells (sometimes expressing MHC class I antigens) and/or stromal cells surrounding tumors (tumor cells) (sometimes also expressing MHC class I antigens; (Dengjel et al .  4163- 70)). The T cells of the present invention are useful as active ingredients in therapeutic compositions. Thus, the present invention also proposes a method of killing a target cell of a patient, wherein the target cell of the patient aberrantly expresses a polypeptide comprising the amino acid sequence of the present invention. The method comprises administering to the patient an effective amount of the above-mentioned tau cell. The term "abnormal expression" as used by the inventors also includes 'overexpression of a polypeptide compared to normal expression levels, or the gene is not expressed in tumor-derived tissues but expressed in the tumor. "Overexpression" means that the polypeptide level is at least 1 - 2 times that in normal tissues; preferably at least 2 times, more preferably at least 5 or 10 times in normal tissues. Purine cells can be made by methods known in the art (e.g., as described above). The sputum cell subsequent transfer protocol is well known in the art and can be found in the following references' for example: (Dudley et al.  850-54; Dudley et al.  2346-57; Rosenberg et al.  889-97; Rosenberg et al.  1676- 80; Yee et al.  16168-73); review (Gattinoni et al.  383-93) and I54845. Doc -124- 201200594 (Morgan et al. Any of the molecules of the present invention (i.e., peptides, nucleic acids, expression vectors, cells, promoter CTLs, sputum cell receptors, or encoding nucleic acids) are beneficial for the treatment of diseases, and are characterized by the evasion of immune responses by cells. Thus, any of the molecules of the present invention can be used as a medicament or for the manufacture of a medicament. Such a molecule may be used alone or in combination with other molecules or known molecules of the present invention. The agent described in the present invention is preferably a vaccine. The vaccine can be given directly to the affected organ of the patient, or it can be Ld. , Lm. , s. c·, ip>iv. Injection is administered systemically, or in vitro to cells from patients or their cell lines (and then injected into patients), or in vitro for a subpopulation of cells from the patient's immune cells (and then the cells) Re-administer the patient). If the nucleic acid is injected into the cell in vitro, it may be beneficial for cell transfection to co-express the immunostimulatory cytokine (eg, interleukin-2). The peptide may be administered alone or in combination with an immunostimulatory adjuvant (see below), or in combination with an immunostimulatory cytokine, or in a suitable delivery system (e.g., liposomes). The peptide may also be conjugated to form a suitable vector, such as keyhole limpet hemocyanin (KLH) or mannose, to a suitable vector (see w〇 95/18145 and Longeneckerl 993). The peptide may also be labeled or may be a fusion protein or a hybrid molecule. The appearance of the peptide sequence in the present invention is expected to stimulate CD4 or CD8 T cells. However, stimulation with CD8 CTL is more effective when cd4T helper cells provide help. Thus, for stimulating MHC class I epitopes of CD8 CTL, a fusion partner or fragment of a hybrid molecule provides an appropriate epitope for stimulating CD4-positive T cells. The CD4j〇 cD8 stimulation epitope is well known in the art and includes the epitopes identified in the present invention. 154845. Doc • 125· 201200594 In one aspect, the vaccine comprises at least one peptide as set forth in SEQ ID ΝΟ: 1 to 33 and at least one other peptide, preferably 2 to 50, more preferably 2 to 25, still more preferably 2 to Fifteen, most preferably 2, 3, 4, 5, 6, 7, 8, 9, 1 〇, 11, 12 or 13 peptides. The peptide may be derivatized from one or more specific TAAs and may bind to mhCI-like molecules. The polynucleotide may be in a substantially purified form or may be coated on a carrier or delivery system. The nucleic acid may be DNA 'cDNA, PNA, CNA, RNA, or a combination thereof. Methods of designing and introducing such nucleic acids are well known in the art. For example, there is an overview in the literature (Pasc〇1〇 et al U7 22). Polynucleotide vaccines are easy to prepare, but the mode of action of these vectors to induce immune responses is not fully understood. "Appropriate vectors and delivery systems include viral DNa and/or RNA, such as adenovirus, vaccinia virus, retrovirus, herpes virus A system of adeno-associated viruses or mixed viruses containing more than one viral element. Non-viral delivery systems include cationic liposomes and cationic polymers, and 疋DNA delivery systems are well known in the art. Physical delivery systems can also be used, such as through "general robbing." The peptide encoded by the peptide or nucleic acid may be a fusion protein', e.g., an epitope containing a stimulating T cell for the above cdr. The agents of the invention may also include one or more adjuvants. Adjuvants are those that non-specifically enhance or potentiate an immune response (eg, an immune response to an antigen mediated by CTL and helper T (TH) cells and are therefore considered useful for the agents of the invention. Agents include, but are not limited to, 1018 ISS, aluminum salts, Amplivax@, AS15, BCG cp_ 870, 893, CPG7909, CyaA, dSLIM, flagellin or flagellin-derived TLR5 ligand, FLT3 ligand, GM-CSF, IC30, 154845. Doc 8 201200594 IC31, ALDARA®, resiquimod, ImuFact IMP321, interleukin IL-2, IL-13, IL-21, interferon alpha or beta, or its polyethylene glycol derivatives, IS Patch, ISS, ISCOMATRIX, ISCOMs, Juvlmmune, LipoVac, MALP2, MF59, Single Disc Rouge A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-5 1, Oil-in-Water and Water-in-Water Emulsion , OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® carrier system, based on polylactide complex glycolide [PLG] and dextran microparticles, recombinant human lactoferrin SRL172 Aquila's QS21 stimulator, viral particles and other virus-like particles, YF-17D, VEGF trap, R848, β-glucan, Pam3Cys, saponins, mycobacterial extracts, and bacterial cell wall synthesis mimics, And other proprietary adjuvants such as Ribi's Detox, Quil or Superfos. Preferred adjuvants are, for example, Freund's adjuvant or GM-CSF. Some dendritic cell-specific immunoadjuvants (such as MF59) and their preparation methods have been described (Allison and Krummel 932-33). Cytokines can also be used. Some cytokines directly affect the migration of dendritic cells to lymphoid tissues (eg, TNF-), and accelerate the maturation of dendritic cells into effective antigen-presenting cells of T lymphocytes (eg, GM-CSF, IL-1, and IL-4). (US Patent No. 5,849,589, specifically incorporated herein by reference) and serving as an immunoadjuvant (WIL-12, IL-15, IL-23, IL-7, IFN-alpha, IFN-p) [Gabrilovich 1996]. It has been reported that CpG immunostimulatory oligonucleotides enhance the role of adjuvants in vaccines. Without theoretical constraints, CpG oligonucleotides can initiate a congenital (non-adaptive) immune system from Toll-like receptors (TLRs) (mainly TLR9) from 154,845. Doc -127- 201200594 And the role of CPG-induced TLR9 activation increases antigen-specific humoral and cellular responses to various antigens, including peptide or protein antigens, live viruses or killed viruses, dendritic cells Vaccines, autologous cell vaccines, and polysaccharide combinations in prophylactic and therapeutic vaccines. More importantly, it enhances the maturation and differentiation of dendritic cells, resulting in enhanced activation of Thi cells and enhanced production of cytotoxic tau lymphocytes (CTLs), even in the absence of CD4 T cells. Even the presence of a vaccine adjuvant maintains the Th|shift induced by TLR9 activation, such as alum or Freund's incomplete adjuvant (IFA), which normally promotes Τη2 shift. CpG oligonucleotides exhibit stronger adjuvant activity when prepared or co-administered with other adjuvants or formulations, such as microparticles, nanoparticles, fat emulsions or similar preparations, when the antigen is relatively weak, these pairs It is especially necessary to induce a strong reaction. They can also accelerate the immune response to reduce the antigen dose by about two orders of magnitude, and in some experiments, a similar antibody response can be produced for CpG-free full-dose vaccines (Kneg 471-84). U.S. Patent 6,406,705 B1 describes the use of CpG oligonucleotides, non-nucleic acid adjuvants, and antigens to promote antigen-specific immune responses. One CpGTLR9 antagonist is dSLIM (double dry loop immunomodulator) from Mologen Corporation (Berlin, Germany), which is a preferred component of the pharmaceutical composition of the present invention. Other TLR binding molecules such as RNA binding TLR7, TLR8 and/or TLR9 can also be used. Other useful adjuvant examples include, but are not limited to, chemically modified CpG (eg, CpR, idera), dsRNA mimics, eg, Poly(I:C) and its derivatives (eg, AmpliGen®, Hiltonol®, multimerization) - (ICLC), poly (IC-R), poly (I: C12U), non-CpG bacterial DNA or RNA and I54845. Doc (S) •128· 201200594 Epidermal active small molecules and antibodies, such as: cyclophosphamide, sunituzumab, bevacizumab, celebrex, NCX_4016, sildenafil, tadalafil, alfalfa Nafia, sorafenib, temSir〇Hmus, Cp_547632, pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other major antibody-targeting major structures of the immune system (eg: Anti-CD40, anti-TGFp, anti-TNFa receptors and 8 (:58175, these drugs may have therapeutic effects and / or act as adjuvants. The skilled person can easily determine the usefulness of the present invention without excessive undue experimentation. Amounts and Concentrations of Adjuvants and Additives 6 Preferred adjuvants are imiquimod, resiquimod, GM-CSF 'cycloheximide, sunitinib, bevacizumab, interferon-a, CpG nucleotides and a microparticle preparation or viral particle of a derivative, t (I:C) and a derivative, RNA, sildenafil, and plg. In a preferred embodiment of the pharmaceutical composition of the present invention, the adjuvant is from a colony-containing stimulation factor preparation Selection, such as granulocyte macrophage colony stimulation factor (GM-CSF 'sagstatin' Imiquimod, resiqUim〇d, and interferon_a ° In a preferred embodiment of the pharmaceutical composition of the present invention, the adjuvant selects from the colony-containing stimulation factor preparation such as granulocyte macrophage colony stimulation factor (GM-CSF) 'Sagstatin', M. militaric and resimiquim 〇d 一个 In a preferred embodiment of the pharmaceutical composition of the invention, the adjuvant is imiprote or resiquimod. The combination drug is for parenteral injection, Such as subcutaneous, intradermal, intramuscular injection, can also be taken orally. For this, peptides and other selective molecules in the pharmaceutically acceptable carrier 154,845. Doc -129- 201200594 Decomposed or suspended, preferably a water carrier. Additionally, the compositions may contain adjuvants such as buffers, binders, impact agents, diluents, perfumes, lubricants and the like. These peptides can also be combined with immunostimulating substances such as cytokines. Further excipients which can be used in such compositions are known from the Handbook 〇f pharmaceutical Excipients by A Kibbe (3rd edition, 2nd year, American Medical Association and Pharmaceutical Press). This combination drug can be used to prevent, prevent and/or treat adenoma or cancerous diseases. There are exemplary formulations in EP 2113253. The present invention proposes an agent which is advantageous for the treatment of cancer, particularly gastric cancer, renal cell carcinoma, colon cancer, non-small cell lung cancer, adenocarcinoma, prostate cancer, benign tumor and malignant melanoma. A kit kit of the present invention further comprises: (a) a container comprising the above-described solution or a pharmaceutical composition in the form of a lyophilized powder; (b) an optional second container containing a lyophilized powder-type diluent Or recombinant > trough; and (c) optional, (1) use of the solution or (ii) instructions for reconstitution and/or use of the lyophilized powder form. The 6-well kit also includes one or more (iii) buffers, (iv) diluent, (v) filtrate, (Vi) needle, or (V) syringe. The container is preferably a bottle, vial, syringe or test tube; it can also be a multi-purpose container. The pharmaceutical combination is preferably a lyophilized powder. The kit of the present invention preferably comprises a Kanggan formulation in a suitable container and instructions for reconstitution and/or use. Suitable containers include, for example, bottles, vials (e.g., dual chamber bottles), syringes (e.g., dual chamber syringes), and test tubes. 154845. Doc •130· 201200594 5 The device can be made of a variety of materials, such as glass or plastic. Preferably, 套件, kits and/or containers are indicated, indicating that recombination and/or use of examples such as 'tags may indicate that the lyophilized dosage form is recombined to the above peptide concentration. This label can further indicate that the formulation is for subcutaneous injection. The trough for storing the formulation may use a multi-purpose vial such that the reconstituted dosage form can be re-administered (e.g., 2-6 times). The kit may further comprise a second container filled with a suitable diluent, such as a sodium bicarbonate solution. After the diluent and the lyophilized preparation are mixed, the final concentration of the peptide in the recombinant preparation is preferably 0. 15 mg/mL/peptide (=75 軏 g), no more than 3 mg/mL/peptide (=1500 軏g). The kit may also include other materials that are commercially and user-friendly, including other buffers, thinners, filters, needles, syringes, and package inserts with instructions for use. The kit of the present invention may have a separate container containing the pharmaceutical composition preparation of the present invention. The preparation may have other ingredients (for example, other compounds or pharmaceutical compositions thereof), or may have no other ingredients, or Each ingredient has its own different container. Preferably, the kit of the invention comprises a formulation with the invention, after armoring with a second compound (such as an adjuvant (eg GM_CSF), a chemotherapeutic drug, a natural product, a hormone or antagonist, an anti-angiogenic agent or inhibition A agent, an apoptosis inducing agent or a chelating agent) or a pharmaceutical composition thereof is used in combination. The components of the kit can be pre-complexed or each component can be placed in a separate container before being administered to a patient. The ingredients of the kit may be one or more solutions, preferably an aqueous solution, more preferably a sterile aqueous solution. The kit may also be in solid form, converted to a liquid by adding a suitable solvent, preferably placed at 154845. Doc 131 201200594 Another different container. The container for the treatment kit may be a vial, test tube, flask, bottle, injection benefit, or any other tool that holds a solid or liquid. Typically, when there are no more than one ingredient, the kit will contain a second vial or other container so that it can be quantified separately. The kit may also contain another grain thief loaded with a medicinal liquid. Preferably, the treatment kit will contain a device (e.g., one or more needles, syringes, eye drops, pipettes, etc.) such that the medicament of the invention (composition of the kit) can be injected. The pharmaceutical formulation of the invention is suitable for peptide administration by any acceptable route 'eg oral (intestinal), intranasal, intraocular, subcutaneous, intradermal, intramuscular, intravenous or transdermal administration, preferably subcutaneous administration Most preferably, it is administered intradermally or by an infusion pump. Since the peptide of the present invention derived from MST1R, UCHL5, SMC4, NFYB, PPAP2C, AVL9, UQCRB and MUC6 is isolated from gastric cancer, the agent of the present invention is preferably used for the treatment of gastric cancer. The following description of the preferred embodiments of the invention will be illustrative (but not limited thereto). For the purposes of the present invention, all references are hereby incorporated by reference in their entirety in each of the entireties in the the the the the the the the the the the the the the the the the the the the the the the the the the the the ) Provided by the Osaka City University Graduate School of Medicine (OCU) in Osaka, Japan. Institute 154845. Doc •132· 8 201200594 Some patients received written informed consent prior to surgery. Tissues were cold shock treated with liquid nitrogen immediately after surgery and stored at -80 °C prior to separation of TUMAP. Isolation of HLA peptides from tissue samples was slightly modified according to protocol, using HLA-A, HLA-B, HLA-C specific antibody W6/32, CNBr activated agarose gel, acid treatment and ultrafiltration method to solid tissue The HLA peptide library of cold shock tissue samples was obtained by immunoprecipitation (Falk, K. 1991; Seeger, F. H. T1999). Methods The obtained HLA peptide library was separated according to its hydrophobicity by reverse phase chromatography (Acquity UPLC system, Waters), and the eluted peptide was analyzed by LTQ-Orbitrap hybridization mass spectrometry (ThermoElectron) equipped with an electrospray source. The peptide library is loaded directly into the fill. The 7 μηι C18 reversed phase material (Waters) was analyzed by a lyotropic quartz microcapillary column (75 μm inner diameter x 250 mm) at a flow rate of 400 nL per minute. Subsequently, the peptide was separated using a two-step 180 minute binary gradient method from a flow rate of 300 nL per minute at a concentration of 10% to 33% solvent B. The gradient is from solvent A (including 0. 1% citric acid water) and solvent B (including 0. 1% formic acid in acetonitrile). A gold coated glass capillary (PicoTip, New Objective) was used to introduce the nanoliter electrospray source. Use the top 5 (TOP5) strategy to operate the LTQ-Orbitrap mass spectrometer in data dependent mode. In short' first, a full scan of high-precision quality begins at orbitrap for one scan cycle (R = 30,000), followed by MS/MS for the five most abundant precursor ions in orbitrap using dynamic exclusion of previously selected ions. Scan (R=7500). Tandem mass spectrometry was performed with SEQUEST and another manual controller 154845. Doc -133· 201200594 Interpretation. The resulting natural peptide fragmentation pattern is compared to the fragmentation pattern of the same reference peptide of the synthetic sequence to ensure the identified peptide sequence. Figure 1 shows a typical spectrum of the MHC class I related peptide CDC2-001 obtained from tumor tissues and its elution profile in a UPLC system. Example 2: Expression profiles of genes encoding the peptides of the present invention Not all peptides identified as being presented to the surface of tumor cells by MHC molecules are suitable for immunotherapy because most of these peptides are expressed by many types of cells. The normal cellular proteins are derived. Only a small fraction of these peptides are tumor-associated and may be able to induce T cells with high specificity for their source of tumor recognition. In order to identify these peptides and minimize the risk of autoimmunity induced by vaccination of these peptides, the inventors primarily employed the morphologies obtained from proteins that were overexpressed on tumor cells (as compared to most normal tissues). The ideal peptide is derived from a protein that is unique to the tumor and does not appear in other tissues. In order to determine a peptide produced by a gene having a similar expression profile to an ideal gene, the identified peptides are separately assigned to proteins and genes, from which genes are obtained and expression profiles of these genes are generated. RNA Sources and Preparation Surgical resection of tissue specimens was provided by two different clinical centers (see Example 1) after obtaining written informed consent from the parent patient. Tumor tissue specimens were quickly frozen in liquid nitrogen immediately after surgery, and then sputum was used in liquid nitrogen. After using TRI5 (Ambion, Darmstadt, Germany), RNeasy (QIAGEN's Hilden, Germany) was used to clean from these samples 154,845. Doc .  134- 8 201200594 Preparation of total RNA; both methods were performed according to the manufacturer's protocol. Total RNA in healthy human tissues is commercially available (Ambion, Huntingdon, UK; Clontech, Heidelberg, Germany; Stratagene, Amsterdam, The Netherlands; BioChain, Hayward, CA, USA). Mix a few individuals (2 to 123 individuals) of RNA so that each person's RNA is equally weighted. White blood cells were isolated from blood samples from four healthy volunteers. The quality and quantity of all RNA samples were evaluated on an Agilent 2100 Bioanalyzer analyzer (Agilent, Waldbronn, Germany) using the RNA6000 Pico LabChip Kit kit (Agilent). Microarray experiments All tumor and normal tissue RNA samples were made using Affymetrix Human Genome (HG) U133A or HG-U133 Plus 2. Gene expression analysis was performed on a 0 Affymetrix oligonucleotide wafer (Affymetrix ' Santa Clara, CA, USA). All steps are performed according to the Affymetrix manual. Briefly, double-stranded cDNA was synthesized from 5-8 pg of RNA using Superscript RTII (Invitrogen) and oligo-dT-T7 primer (MWG Biotech, Ebersberg, Germany) as described in the manual. U133A was measured with BioArray High Yield RNATranscript Labelling Kit (ENZO Diagnostics, Inc., Farmingdale, NY, USA) or U133 Plus with GeneChip IVT Labelling Kit (Affymetrix). 0 assay followed by streptavidin-phycoerythrin and biotinylated anti-streptomycin antibody (Molecular Probes, Leiden, 154845. Doc -135- 201200594 lan) performs disruption, hybridization and staining to complete in vitro transcription. Use Agilent 2500A GeneArray Scanner (U133A) or Affymetrix Gene-Chip Scanner 3000 (U133 Plus 2. 0) Scan the image and analyze the data with GCOS software (Affymetrix) with default settings for all parameters. To standardize, 100 housekeeping genes from Affymetrix were used. The relative expression values were calculated using the signal log ratio given by the software. The value of the normal kidney tissue sample was arbitrarily set to 1. 0. The expression profile of the highly expressed gene of the present invention in gastric cancer is shown in Fig. 2. Example 3: In vitro immunogenicity of IMA941MHC-I-presented peptides In order to obtain information on the immunogenicity of TUMAP of the present invention, we used Walter, S, Herrgen, L, Schoor, Ο, Jung, G, Wernet. D, Buhring, HJ, Rammensee, HG and Stevanovic, S et al. 2003 in Cutting edge: predetermined avidity of human CD8T cells expanded on calibrated MHC/anti-CD28-coated microspheres, J. Immunol. , 171, 4974-4978 - The widely accepted in vitro stimulation platform described in the paper was studied. In this way, the 32 HLA-A*2402-restricted TUMAPs of the present invention all showed immunogenicity, indicating that these peptides are T cell epitopes against human CD8+ precursor T cells (Table 4). CD8+ T cells are activated in vitro in order to use artificial 154845 carrying peptide-MHC complex (pMHC) and anti-CD28 antibody. Doc -136- 201200594 Antigen-presenting cells (aAPC) were stimulated in vitro. We first isolated fresh HLA-A*24 products from healthy donor leukocyte clearance from the Tuebingen blood bank to isolate CD8 T cells. Then, the product obtained by leukapheresis is directly enriched with CD8 T cells, or PBMC (peripheral blood mononuclear cells) is first isolated using standard gradient separation medium (PAA, C6lbe, Germany). The isolated CD8 lymphocytes were cultured in T cell culture medium (TCM) before use. The culture medium was coated with RPMI-Glutamax (Invitrogen, Karlsruhe, Germany) and supplemented with 10% heat-killed human AB jk clear (PAN-Biotech , Aidenbach, Germany), 100 U/ml penicillin/100 pg/ml streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, Germany) and 20 pg/ml gentamicin (Cambrex). In this step, 2. 5 ng/ml IL-7 (PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma, Niirnberg, Germany) were also added to TCM. CD8+ lymphocytes were isolated by positive selection using MicroBeads (Miltenyi Biotec, Bergisch-Gladbach, Germany). Generation of pMHC/anti-CD28 coated beads, T cell stimulation and readout methods as previously described (Walter et al.  4974-78) with minor modifications. Briefly, a biotinylated peptide recombinant HLA-A*2402 molecule lacking a transmembrane domain and biotinylated at the carboxy terminus of the heavy chain was prepared. Purified co-stimulated mouse IgG2a anti-human CD28 antibody 9. 3 (Jung, Ledbetter, and Muller-Eberhard 4611, 15) Chemical biotinylation using N-hydroxysuccinimide biotin recommended by the manufacturer (Perbio, Bonn, Germany). The beads used are 5. 6 μπι 154845. Doc-137-201200594 Large streptavidin-coated polystyrene particles (Bangs Labooratories, Ill., USA). The pMHC as a control were A*0201/MLA-001 (peptide ELAGIGILTV prepared from modification in Melan-A/MART-Ι) and A*0201/DDX5-001 (YLLPAIVHI obtained from DDX5). 800. 000 beads/200 μΐ were wrapped in 96-well plates and were present in 600 ng biotin anti-CD28 + 200 ng related biotin pMHC (high density beads). lxlO6 CD8+ T cells and 2 χ 105 washcoat beads were co-cultured in 200 μΐ TCM containing 5 ng/ml IL-12 (PromoCell) for 3 to 4 days at 37 ° C to initiate stimulation in 96-well plates. Thereafter, half of the medium was exchanged with fresh TCM supplemented with 80 U/ml IL-2, and culture was continued for 3 to 4 days at 37 ° C. This stimulation cycle was performed a total of 3 times. Finally, multimerization was performed with Live/dead-Aqua dye (Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD company, Heidelberg, Germany) and PE- or APC-coupled A*2402 MHC multimer staining. Body analysis. For the analysis, a BD LSRII SORP cytometer equipped with a suitable laser and screening procedure was used. Peptide-specific cells were calculated as a percentage of total CD8+ cells. Multimeric analysis results were evaluated using FlowJo software (Tree Star, Oregon, USA). In vitro filling of specific multimer + CD8+ lymphocytes was performed using appropriate gating techniques as well as comparison with the negative control stimulation group. If at least one evaluable in vitro stimulation well in a healthy donor is found to contain a specific CD8+ T cell line after stimulation in vitro (ie, the well comprises at least 1% specific multimer + CD8+ T cells, and the specific polymer The percentage of + is at least 10 times the median of the negative control stimulus, and the test is given 154845. Doc -138- 8 201200594 The immunogenicity of the antigen. Immunogenicity of the IMA94 1 peptide for 47 of the 54 tested HLA-A*2402 peptides and 3 of the 3 tested HLA-A*0201 peptides, by generating peptide-specific T cells Strain to demonstrate in vitro immunogenicity. An exemplary flow cytometer result of the two peptides of the invention and the corresponding negative controls after staining with TUMAP-specific polymers is shown in Figure 3. The results of the 54 A*2402 and 3 A*0201 of the present invention are summarized in Table 4. Table 4: In vitro immunogenicity of HLA class I peptides in the present invention The results of in vitro immunogenicity experiments performed by Immatics show the percentage of positive tested donors and plate wells evaluated. At least four donors and 48 wells were evaluated per peptide. SEQ ID NO: antigen positive donor/tested donor [%] positive well/tested well [%1 1 CDC2-001 83 28 2 ASPM-002 67 32 18 MMP3-001 11 1 4 MET-006 67 21 3 UCHL5-001 75 12 7 MST1R-001 50 13 33 KIF2C-001 17 2 9 SMC4-001 73 10 17 EPHA2-005 0 0 5 PROM 1-001 83 26 6 MMP11-001 33 11 8 NFYB-001 50 7 16 ASPM -001 17 3 20 PLK4-001 60 5 154845. Doc -139- 201200594 14 ABL1-001 83 18 26 ATAD2-001 33 3 21 ATAD2-002 17 1 27 ATAD2-003 0 0 12 AVL9-001 100 31 22 COL12A1-001 0 0 23 COL6A3-001 0 0 24 FANCI- 001 17 1 28 HSP90B1-001 50 7 15 MUC6-001 83 22 13 NUF2-001 100 50 19 NUF2-002 50 6 11 PPAP2C-001 83 29 25 RPS11-001 17 3 29 SIAH2-001 50 8 30 SLC6A6-001 17 1 10 UQCRB-001 83 24 31 IQGAP3-001 100 24 32 ERBB3-001 83 CCDC88A-001 0 0 CCNB1-003 33 3 CCND2-001 17 10 CCNE2-001 0 0 CEA-010 40 3 CLCN3-001 33 6 DNAJC10- 001 50 15 DNAJC10-002 33 3 EIF2S3-001 17 1 EIF3L-001 100 29 EPPK1-001 17 1 GPR3 9-001 50 6 ITGB4-001 67 20 LCN2-001 17 1 SDHC-001 33 3 154845. Doc •140- 8 201200594 PBK-001 0 0 POLD3-001 67 7 PSMD14-001 17 1 PTK2-001 17 4 TSPAN1-002 17 1 ZNF598-001 83 17 The following peptides are described in other applications by Immatics and are included in Vaccines IMA901 (MET-001 and TOP-001), IMA910 (MET-001 and TOP-001) and IMA950 (IGF2BP3-001). For example, ΜΕΤ-00 1 can lead to particularly good in vivo reactions, and this result can be considered as clinically useful evidence as a peptide of the present invention. SEQ ID NO: antigen-positive donor/tested donor [%] positive well/tested well ί%1 IGF2BP3-001 50 21 MET-001 67 42 TOP-OO1 40 10 Results of in vitro immunogenicity experiments performed The percentage of positive donors and plate wells evaluated is shown. Evaluate at least four donors and 48 plate wells per peptide. References

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Zhu, KJ, et al. "Imiquimod inhibits the differentiation but enhances the maturation of human monocyte-derived dendritic cells." Int Immunopharmacol. 9.4(2009): 412-17. [Simple illustration] Figure 1: Confirmation of CDC2 -001 is presented as a representative mass spectrum of the primary tumor sample GC2464. NanoESI-LCMS was performed on a library obtained by eluting from GC sample 2464. Quality chromatogram m/z 597.3501 ± 0.001 Da, z=2 dynaminic peptide peaked at retention time of 1 5 1.63 minutes B) The peak value was detected at 153.63 minutes in the quality chromatogram, and the signal was m/ in the ^^ spectrum. z 597·3 501. c) The collision-induced decay mass spectrum of the selected scorpion recorded in the nanoESI-LCMS experiment was m/z 597 35〇1, confirming the presentation of CDC2 〇〇1 in the GC2464 tumor sample. D) Synthesis of CDC2 〇〇1 Ref. 154845.doc * 172 - 201200594 The fragmentation mode of the peptide was recorded and the natural TUMAP fragmentation mode shown in C was used to verify the sequence. Figure 2: Expression profiles of selected protein mRNA in normal tissues and 25 gastric cancer samples a) CDC2 (Probeset ID: 2032 13_at) • b) ASPM (Probeset ID: 2 1991 8_s_at) . Figure 3: Class I TUMAP peptide specific Typical results of in vitro immunogenicity. C D 8+ T cells were introduced with human antigen presenting cells containing relevant (left panel) and unrelated (map), respectively. After 3 cycles of stimulation, peptide-reactive cells were detected by correlated and unrelated A*2402-polymer double staining. The indicated cells were gated on live CD8+ lymphocytes, and the numbers in the figure represent the percentage of multimeric positive cells. 154845.doc -173 - 201200594 Sequence Listing <110> Deutsche Amytik Biotech Co., Ltd. <120> New immunotherapy including several tumors of gastrointestinal and gastric cancer <130> I31890TW <150><;151> GB1004551.6 2010-03-19 <150><151> US 61/315,704 2010-03-19 <;160> 95 <170> Patentln version 3.5 <210><211>;212><213><400> 1 10 PRT Homo sapiens 1

Leu Tyr Gin lie Leu Gin Gly lie Val Phe 15 10 <210><211> 2 9 <212><213> PRT Homo sapiens <400> 2

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Asn Tyr Leu Pro Phe lie Met Glu Leu 1 5 <210><211><212><213> 4 9 PRT Homo sapiens <400> 4

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Val Trp Ser Asp Val Thr Pro Leu Thr Phe 15 10 <210> 7 <211> 9

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Asn Tyr Leu Leu Tyr Val Ser Asn Phe 1 5 <210〉 8 <211> 9

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Ala Tyr Leu Val Tyr Thr Asp Arg Leu . i 5 <210> ' <211> 12 9 <212><213> PRT Homo sapiens <-300> 12

Phe Tyr lie Ser Pro Val Asn Lys Leu 1 5 <210> 13 <211><212><213> 9 PRT Homo sapiens <400> 13

Val Tyr Gly lie Arg Leu Glu His Phe 1 5 <210><211><212> ' <213> 14 9 PRT Homo sapiens <400> 14

Thr Tyr Gly Asn Leu Leu Asp Tyr Leu 1 5 <210><211><212><213> 15 9 PRT Homo sapiens <400> 15

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Val Tyr Phe Ser Lys Ser Glu Gin Leu 1 5 <210> 18 <211><212><213> 9 PRT Homo sapiens <400> 18

Val Phe lie Phe Lys Gly Asn Gin Phe 1 5 <210><211><212><213> 19 9 PRT Homo sapiens <400> 19

Arg Phe Leu Ser Gly lie lie Asn Phe 1 5 <210><211><212><213> 20 9 PRT · Homo sapiens <400> 20

Gin Tyr Ala Ser Arg Phe Val Gin Leu 1 5 <210> 21 <211><212><213> 9 PRT Homo sapiens <400> 21 154845 - Sequence Listing.doc -4- 8 201200594

Lys Tyr Leu Thr Val Lys Asp Tyr Leu 1 5 <210><211> 22 9

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Val Tyr Asn Pro Thr Pro Asn Ser Leu 1 5 <210><211><212><213> 23 9 PRT Homo sapiens <400> 23

Ser Tyr Leu Gin Ala Ala Asn Ala Leu 1 5 <210><211><212><213> 24 9 PRT Homo sapiens <400> 24

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Lys Tyr Asn Asp Thr Phe Trp Lys Glu Phe 15 10 <210> 29

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Val Phe Asp Thr Ala lie Ala His Leu Phe 15 10 <210> 30 <211> 9

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Val Tyr Pro Asn Trp Ala lie Gly Leu 1 5 <210> 31 <211> 9

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Val Tyr Lys Val Val Gly Asn Leu Leu 1 5 <210> 32 <211> 9

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Arg Tyr Leu Glu Gly Thr Ser Cys lie 1 5 <210><211〉<212><:213> 45 11 PRT Homo sapiens <400> 45

Thr Tyr Leu Pro Thr Asn Ala Ser Leu Ser Phe 15 10 <210><211><212><213> 46 9 PRT Homo sapiens <400> 46

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Ser Tyr Asn Val Thr Ser Val Leu Phe 1 5 <210><211> 49 9 <212><213> PRT Homo sapiens <400> 49

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Leu Tyr Leu Glu Asn lie Asp Glu Phe 1 5 <210> 52 <211〉 9

<212> PRT <213> Homo sapiens <400> 52

Val Tyr lie Ser Ser Leu Ala Leu Leu 1 5 <210〉 53

<211> 11 <212> PRT <213> Homo sapiens <400> 53

Arg Tyr Leu Pro Lys Gly Phe Leu Asn Gin Phe 15 10 <210> 54 <211> 9

<212> PRT <213> Homo sapiens <400> 54

Tyr Tyr Lys Asn lie Gly Leu Gly Phe 1 5 <210> 55 <211> 9 <212> PRT <213> Homo sapiens 154845 - Sequence Listing.doc • 10· 8 201200594 <400&gt ; 55

Val Tyr Thr Thr Met Ala Glu His Phe 1 5 <210> 56 <211><212><213> 9 PRT Homo sapiens <400> 56

Asp Tyr Ala Tyr Leu Arg Glu His Phe 1 5 <210> 57 ' <211><212><213> 10 PRT Homo sapiens <400> 57

Leu Tyr lie Gin Thr Asp His Leu Phe Phe 15 10 <210> 58 <211><212><2:L3> 10 PRT Homo sapiens <400>

Thr Tyr Lys Tyr Val Asp lie Asn Thr Phe 1 5 10 <210> 59 <211><212><213> 9 PRT Homo sapiens <400> 59

Tyr Phe lie Ser His Val Leu Ala Phe 1 5 <210><211><212><213:> 60 9 PRT Homo sapiens <400> 60

Val Tyr Thr Lys Val Ser Ala Tyr Leu 1 5 <210> 61 -11- 154845 - Sequence Listing.doc 201200594 <211> 9 <212><213> PRT Homo sapiens <400> 61

Val Tyr Lys Glu Thr Cys lie Ser Phe 1 5 <210> 62 <211> <212〉 <213> 9 PRT Homo sapiens <400> 62

Ala Leu Tyr Asp Ser Val lie Leu Leu 1 5 <210><211><212><213> 63 9 PRT Homo sapiens <400> 63

Lys lie Gin Glu lie Leu Thr Gin Val 1 5 <210><211><212><213> 64 9 PRT Homo sapiens <400> 64

Leu Ala Asp Glu Thr Leu Leu Lys Val 1 5 <210><211><212><213> 65 9 PRT Homo sapiens <400> 65

Ala Met Ser Ser Lys Phe Phe Leu Val 1 5 <210><211><212〉<213> 66 9 PRT Homo sapiens <400> 66 154845 · Sequence Listing.doc 12- 8 201200594

Tyr Val Tyr Gin Asn Asn lie Tyr Leu 1 5 <210><211> 67 9

<212> PRT <213> Homo sapiens <400> 67

Val Leu Glu Asp Leu Glu Val Thr Val 1 5 <210><211> _ <212> ' <213> 68 9 PRT Homo sapiens <400> 68

Phe Leu Leu Asp Gly Ser Ala Asn Val 1 5 <210><211><212><213> 69 9 PRT Homo sapiens <4Q0> 69

Asn Leu Leu Asp Leu Asp Tyr Glu Leu 1 5 <210><211><212><213> 70 9 PRT f Homo sapiens ' <400> 70

Phe Leu lie Asp Ser Ser Glu Gly Val • 1 5 <210><211><212><213> 71 9 PRT Homo sapiens <400> 71

Ala Leu Asp Glu Gly Asp lie Ala Leu

1 5 , <210>_<211><212〉 72 11 PRT -13- 154845· Sequence Listing.doc 201200594 <213> Homo sapiens <400> 72

Ala Leu Asn Glu Glu Ala Gly Arg Leu Leu Leu 1 5 10 <210><211><212><213> 73 9 PRT Homo sapiens <400> 73 lie Leu Ser Pro Thr Val Val Ser lie 1 5 <210> 74 <211><212><213> 9 PRT Homo sapiens <400> 74

Lys Leu Leu Thr Glu Val His Ala Ala 1 5 <210><211><212><213> 75 9 PRT Homo sapiens <400> 75

Ala Leu Val Gin Asp Leu Ala Lys Ala 1 5 <210><211><212><213> 76 9 PRT Homo sapiens <400> 76 lie Leu Gin Asp Arg Leu Asn Gin Val 1 5 <210><211><212><213> ΊΊ 9 PRT Homo sapiens <400> 77

Thr Leu Asp Pro Arg Ser Phe Leu Leu 1 5 154845 - Sequence Listing.doc 14· 8 201200594 <210> 78 <211><212><213> 9 PRT Homo sapiens <400> 78

Thr Leu Asp Asp Leu Leu Leu Tyr lie 1 5 <210〉 <211><:212><213> 79 11 PRT Homo sapiens <400> Ί9

Ser Leu Leu Ala Gin Asn Thr Ser Trp Leu Leu 1 5 10 <210><211><212〉<213> 80 9 PRT Homo sapiens <400> 80

Ser Leu Ala Glu Val Asn Thr Gin Leu 1 5 <210><211><212><213> 81 9 PRT Homo sapiens <400> 81

Ala Leu Asp Gly Phe Val Met Val Leu 1 5 <210><21i><212><213> 82 9 PRT Homo sapiens <400> 82

Gly Val Asp Asp Ala Phe Tyr Thr Leu 1 5 <210><211> 83 9 <212> , <213> PRT Homo sapiens .1 <400> 83 -15- 154845- List.doc 201200594

Tyr Val Asp Pro Val lie Thr Ser lie 1 5 <210> 84 <211> 9

<212> PRT <213> Homo sapiens <400> 84

Tyr Leu Leu Ser Tyr lie Gin Ser lie 1 5 <210〉 85 <211> 9

<212> PRT <213> Homo sapiens <_> 85

Gin lie Asp Asp Val Thr lie Lys lie 1 5

<210> 86 <211> 10 <212> PRT <213> A (Homo sapiens) <400> 86

Tyr Leu Tyr Gly Gin Thr Thr Thr Tyr Leu 15 10 <210> 87 <211> 9

<212> PRT <213> Homo sapiens <400> 87

Lys Leu Asp Glu Thr Gly Asn Ser Leu 1 5 <210> 88 <211> 9

<212> PRT <213> Homo sapiens <400> 88

Arg Leu Asp Asp Leu Lys Met Thr Val 1 5 <210> 89 <211> 9 •16- 154845 - Sequence Listing.doc 201200594

<212> PRT <213> Homo sapiens <400> 89

Leu Thr Asp Glu lie Leu Thr Tyr Val 1 5 <210><211><212><213> 90 9 PRT Homo sapiens <400> 90 lie Leu lie Asp Trp Leu Val Gin Val 1 5 <210><211><212><213> 91 10 PRT Homo sapiens <400> 91

Val Leu Tyr Gly Pro Asp Val Pro Thr lie 1 5 10 <210><2:L1><212〉<213> 92 11 PRT Homo sapiens <400> 92

Ser lie Phe Gly Glu Asp Ala Leu Ala Asn Val 1 5 10 <210><21;L> 93 9 <212><213> PRT Homo sapiens <400>

Lys Leu Leu Glu Tyr lie Glu Glu lie 1 5 <210><211><212><213> 94 9 PRT Homo sapiens <400> 94

Lys lie Leu Glu Asp Val Val Gly Val 1 5 •17- 154845 - Sequence Listing.doc 201200594 <210> 95

<211> 10 <212> PRT <213> Homo sapiens <400> 95

Lys lie Phe Asp Glu lie Leu 1 5 Val Asn Ala 10 154845 - Sequence Listing.doc 8 8

Claims (1)

201200594 VII. Patent Application Range: 1 - A peptide comprising a sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 95, or a redundant ID No. 1 to SEQ ID No. 95 A variant having 80% homology, or a variant thereof that induces a T cell cross-reactivity with the peptide, wherein the peptide is not a full length polypeptide. 2. A peptide according to claim 1 wherein the peptide has a total length of from 8 to 100 amino acids, preferably from 8 to 30 amino acids, and most preferably from 8 to 14 amino acids. 3. A peptide according to any one of claims 1 or 2 which has the ability to bind to a major tissue compatibility complex (MHC) class I or class II molecule. The peptide according to any one of claims 1 to 3, wherein the peptide consists of or consists essentially of the amino acid sequence selected according to SEQ ID NO 1 to SEQ ID NO 95. The peptide according to any one of claims 1 to 5, wherein the peptide is modified and/or comprises a non-peptide bond. 6. The form according to any one of claims 1 to 5, wherein the peptide is a fusion protein', particularly an N-terminal amino group containing an HLA-DR antigen-associated invariant chain (Π). A nucleic acid encoding a peptide according to any one of claims 1 to 6 if the peptide is not a complete human protein. 8. A nucleic acid according to claim 7, which may be dnA, cDNA, PNA, CAN, RNA' or a combination thereof. 9. An expression vector capable of expressing a nucleic acid according to claim 7 or 8. 154845.doc 201200594 1 〇. A peptide according to any one of claims 1 to 6, a nucleic acid according to any one of claims 7 or 8, or an expression according to claim 9. Carrier. 11. A host cell according to claim 7 or 8 or an expression vector according to claim 9. 12. A host cell which is an antigen presenting cell according to claim 11. 13. The host cell of claim 12, wherein the antigen presenting cell is a dendritic cell. 14. A method of preparing a peptide according to any one of claims 1 to 6, which comprises isolating a peptide from a host cell or a culture medium thereof according to the cultured host cell of claim 11. 15. A method for the preparation of activated cytotoxic tau lymphocytes (CTLs) in vitro, the method comprising: in vitro linking a CTL to an antigen-loaded human I or π-type MHC molecule, the molecules present on the surface of a suitable antigen presenting cell The expression is sufficient for a period of time to initiate Ctl in an antigen-specific manner, wherein the antigen is a peptide as claimed in any one of claims 1 to 6. 16. A method according to claim 15 wherein the antigen is loaded into a class I or class II MHC molecule expressed on the surface of a suitable antigen presenting cell by binding to a sufficient amount of antigen comprising the antigen-presenting cell. 17. The method of claim 15, wherein the antigen presenting cell comprises an expression vector capable of expressing a peptide comprising SEQ ID N〇 1 to SEQ ID NO 95 or the variant amino acid sequence. 18. The method according to any one of claims 15 to 17, wherein the cytotoxicity T site P. h Bibm A polypeptide of a given amino acid sequence. A nucleic acid sequence; a method of administration, which requires a given amount of ammonia in any of 1 to 4, which comprises administering to the patient an effective amount of cytotoxic tau lymphocytes (CTL) as defined in claim 15. The use of the peptide according to any one of claims 1 to 6, the use of a nucleic acid according to claim 7 or 8, the use of an expression vector according to claim 9, Use of a cell according to any of claims 11 to 13, a use as a medicament or a medicament for the initiation of cytotoxic T lymphocytes according to claim 18. 2. Use according to claim 20 wherein the agent is a vaccine. 22. Use according to claim 2 or 21 wherein the agent has anti-cancer activity. 23. The use according to claim 22, wherein the cancer cell is a gastric cancer cell, a gastrointestinal cancer cell, a colorectal cancer cell, a pancreatic cancer cell, a lung cancer cell, or a renal cancer cell. 154845.doc